4-aminoquinazolin-2-yl-1-pyrrazole-4-carboxylic acid compounds as prolyl hydroxylase inhibitors

ABSTRACT

Aminoquinazolinyl compounds of formula (I) are described, which are useful as prolyl hydroxylase inhibitors. Such compounds may be used in pharmaceutical compositions and methods for the treatment of disease states, disorders, and conditions mediated by prolyl hydroxylase activity. Thus, the compounds may be administered to treat, e.g., anemia, vascular disorders, metabolic disorders, and wound healing.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a national phase of International Application No.PCT/US2011/047626 filed Aug. 12, 2011, and claims benefit of priority ofU.S. Provisional Application No. 61/373,664 filed on Aug. 13, 2010.

FIELD OF THE INVENTION

The present invention relates to certain aminoquinazolinyl compounds,pharmaceutical compositions containing them, and methods of using themfor the treatment of disease states, disorders, and conditions mediatedby prolyl hydroxylase activity.

BACKGROUND OF THE INVENTION

Cells respond to hypoxia by activating the transcription of genesinvolved in cell survival, oxygen delivery and utilization,angiogenesis, cellular metabolism, regulation of blood pressure,hematopoiesis, and tissue preservation. Hypoxia-inducible factors (HIFs)are key transcriptional regulators of these genes (Semenza et al., 1992,Mol Cell Biol., 12(12):5447-54; Wang et al., 1993, J Biol Chem.,268(29):21513-18; Wang et al., 1993, Proc Natl Acad. Sci., 90:4304-08;Wang et al., 1995, J Biol Chem., 270(3):1230-37). Three forms of HIF-αhave been described: HIF-1α, HIF-2α and HIF-3α (Scheuermann et al.,2007, Methods Enzymol., 435:3-24). Pairing of a HIFα sub-unit withHIF-1β forms a functional heterodimeric protein that subsequentlyrecruits other transcriptional factors such as p300 and CBP (Semenza,2001, Trends Mol Med., 7(8):345-50).

A family of highly conserved oxygen, iron, and 2-oxoglutarate-dependentprolyl hydroxylase (PHD) enzymes mediate the cells response to hypoxiavia post-translational modification of HIF (Ivan et al., 2001, Science,292:464-68; Jaakkola et al., 2001, Science, 292:468-72). Under normoxicconditions, PHD catalyzes the hydroxylation of two conserved prolineresidues within HIF. Von Hippel Lindau (VHL) protein binds selectivelyto hydroxylated HIF. The binding of VHL renders HIF a target forpolyubiquitination by the E3 ubiquitin ligase complex and its subsequentdegradation by the 26S proteasome (Ke et al., 2006, Mol Pharmacol.70(5):1469-80; Semenza, Sci STKE., 2007, 407(cm8):1-3). As the affinityof PHD for oxygen is within the physiological range of oxygen and oxygenis a necessary co-factor for the reaction, PHD is inactivated whenoxygen tension is reduced. In this way, HIF is rapidly degraded undernormoxic conditions but accumulates in cells under hypoxic conditions orwhen PHD is inhibited.

Four isotypes of PHD have been described: PHD1, PHD2, PHD3, and PHD4(Epstein et al., 2001, Cell, 107:43-54; Kaelin, 2005, Annu Rev Biochem.,74:115-28; Schmid et al., 2004, J Cell Mol Med., 8:423-31). Thedifferent isotypes are ubiquitously expressed but are differentiallyregulated and have distinct physiological roles in the cellular responseto hypoxia. There is evidence that the various isotypes have differentselectivity for the three different HIFα sub-types (Epstein et al.,supra). In terms of cellular localization, PHD1 is primarily nuclear,PHD2 is primarily cytoplasmic, and PHD3 appears to be both cytoplasmicand nuclear (Metzen E, et al. 2003, J Cell Sci., 116(7):1319-26). PHD2appears to be the predominant HIFα prolyl hydroxylase under normoxicconditions (Ivan et al., 2002. Proc Natl Acad. Sci. USA,99(21):13459-64; Berra et al., 2003, EMBO J., 22:4082-90). The threeisotypes have a high degree of amino-acid homology and the active siteof the enzyme is highly conserved.

The HIF target gene products are involved in a number of physiologicaland pathophysiological processes including but not limited to:erythropoiesis, angiogenesis, regulation of energy metabolism, vasomotorfunction, and cell apoptosis/proliferation. The first gene described asa HIF target was that encoding erythropoietin (EPO) (Wang et al., 1993,supra). It was recognized that a reduction in the oxygen carryingcapacity of the blood is sensed in the kidney and that the kidney andliver respond by releasing more EPO, the hormone that stimulates redblood cell proliferation and maturation. EPO has a number of otherimportant effects on non-hematopoietic cell types and has emerged as akey tissue-protective cytokine (Arcasoy, 2008, Br J Haematol.,141:14-31). Thus EPO is now implicated in wound healing and angiogenesisas well as the response of tissues to ischemic insult. Most of theenzymes involved in anaerobic glycolysis are encoded by HIF target genesand as a result glycolysis is increased in hypoxic tissues (Shaw, 2006,Curr Opin Cell Biol., 18(6):598-608). The known HIF target gene productsin this pathway include but are not limited to: glucose transporterssuch as GLUT-1 (Ebert et al., 1995, J Biol Chem., 270(49):29083-89),enzymes involved in the breakdown of glucose to pyruvate such ashexokinase and phosphoglycerate kinase 1 (Firth et al., 1994, Proc NatlAcad Sci. USA, 91:6496-6500) as well as lactate dehydrogenase (Firth etal., supra). HIF target gene products are also involved in theregulation of cellular metabolism. For example, pyruvate dehydrogenasekinase-1 is a target HIF gene product and regulates the entry ofpyruvate into the Kreb's cycle by reducing the activity of pyruvatedehydrogenase by phosphorylation (Kim et al., 2006, Cell Metab.,3:177-85; Papandreou et al., 2006, Cell Metab., 3:187-197). HIF targetgene products are also involved in angiogenesis. For example, vascularendothelial growth factor (VEGF) (Liu et al., 1995, Circ Res.,77(3):638-43) is a known regulator of angiogenesis and vasculogenesis.HIF target gene products also function in the regulation of vasculartone and include heme oxygenase-1 (Lee et al., 1997, J Biol Chem.,272(9):5375-81). A number of HIF regulated gene products such asplatelet-derived growth factor (PDGF) (Yoshida et al., 2006, JNeurooncol., 76(1):13-21), vascular endothelial growth factor (Breen,2007, J Cell Biochem., 102(6):1358-67) and EPO (Arcasoy, supra) alsofunction in the coordinated response to wound healing.

Targeted disruption of the prolyl hydroxylase (PHD) enzyme activity bysmall molecules has potential utility in the treatment of disorders ofoxygen sensing and distribution. Examples include but are not limitedto: anemia; sickle cell anemia; peripheral vascular disease; coronaryartery disease; heart failure; protection of tissue from ischemia inconditions such as myocardial ischemia, myocardial infarction andstroke; preservation of organs for transplant; treatment of tissueischemia by regulating and/or restoring blood flow, oxygen deliveryand/or energy utilization; acceleration of wound healing particularly indiabetic and aged patients; treatment of burns; treatment of infection;bone healing, and bone growth. In addition, targeted disruption of PHDis expected to have utility in treating metabolic disorders such asdiabetes, obesity, ulcerative colitis, inflammatory bowel disease andrelated disorders such as Crohn's disease. (Recent Patents onInflammation & Allergy Drug Discovery, 2009, 3, 1-16).

HIF has been shown to be the primary transcriptional factor that leadsto increased erythropoietin production under conditions of hypoxia (Wanget al., 1993, supra). While treatment with recombinant humanerythropoietin has been demonstrated to be an effective method oftreating anemia, small molecule mediated PHD inhibition can be expectedto offer advantages over treatment with erythropoietin. Specifically,the function of other HIF gene products are necessary for hematopoesisand regulation of these factors increases the efficiency ofhematopoesis. Examples of HIF target gene products that are critical forhematopoesis include: transferrin (Rolfs et al., 1997, J Biol Chem.,272(32):20055-62), transferrin receptor (Lok et al., 1999, J Biol Chem.,274(34):24147-52; Tacchini et al., 1999, J Biol Chem., 274(34):24142-46)and ceruloplasmin (Mukhopadhyay et al., 2000, J Biol Chem.,275(28):21048-54). Hepcidin expression is also suppressed by HIF(Peyssonnaux et al., 2007, J Clin Invest., 117(7):1926-32) and smallmolecule inhibitors of PHD have been shown to reduce hepcidin production(Braliou et al., 2008, J Hepatol., 48:801-10). Hepcidin is a negativeregulator of the availability of the iron that is necessary forhematopoesis, so a reduction in hepcidin production is expected to bebeneficial to the treatment of anemia. PHD inhibition may also be usefulwhen used in conjunction with other treatments for anemia including ironsupplementation and/or exogenous erythropoietin. Studies of mutations inthe PHD2 gene occurring naturally in the human population providefurther evidence for the use of PHD inhibitors to treat anemia. Tworecent reports have shown that patients with dysfunctional mutations inthe PHD2 gene display increased erythrocytosis and elevated bloodhemoglobin (Percy et al., 2007, PNAS, 103(3):654-59; Al-Sheikh et al.,2008, Blood Cells Mol Dis., 40:160-65). In addition, a small moleculePHD inhibitor has been evaluated in healthy volunteers and patients withchronic kidney disease (U.S. pat. appl. US2006/0276477, Dec. 7, 2006).Plasma erythropoietin was increased in a dose-dependent fashion andblood hemoglobin concentrations were increased in the chronic kidneydisease patients.

Metabolic adaptation and preservation of tissues are jeopardized byischemia. PHD inhibitors increase the expression of genes that lead tochanges in metabolism that are beneficial under ischemic conditions(Semenza, 2007, Biochem J., 405:1-9). Many of the genes encoding enzymesinvolved in anaerobic glycolysis are regulated by HIF and glycolysis isincreased by inhibiting PHD (Shaw, supra). Known HIF target genes inthis pathway include but are not limited to: GLUT-1 (Ebert et al.,supra), hexokinase, phosphoglycerate kinase 1, lactate dehydrogenase(Firth et al., supra), pyruvate dehydrogenase kinase-1 (Kim et al.,supra; Papandreou et al., supra). Pyruvate dehydrogenase kinase-1suppresses the entry of pyruvate into the Kreb's cycle. HIF mediates aswitch in the expression of the cytochromes involved in electrontransport in the mitochondria (Fukuda et al., 2007, Cell,129(1):111-22). This change in the cytochrome composition optimizes theefficiency in ATP production under hypoxic conditions and reduces theproduction of injurious oxidative phosphorylation by-products such ashydrogen peroxide and superoxide. With prolonged exposure to hypoxia,HIF drives autophagy of the mitochondria resulting in a reduction intheir number (Zhang H et al., 2008, J Biol Chem. 283: 10892-10903). Thisadaptation to chronic hypoxia reduces the production of hydrogenperoxide and superoxide while the cell relies on glycolysis to produceenergy. A further adaptive response produced by HIF elevation isup-regulation of cell survival factors. These factors include:Insulin-like growth factor (IGF) 2, IGF-binding protein 2 and 3 (Feldseret al., 1999, Cancer Res. 59:3915-18). Overall accumulation of HIF underhypoxic conditions governs an adaptive up-regulation of glycolysis, areduction in oxidative phosphorylation resulting in a reduction in theproduction of hydrogen peroxide and superoxide, optimization ofoxidative phosphorylation protecting cells against ischemic damage.Thus, PHD inhibitors are expected to be useful in organ and tissuetransplant preservation (Bernhardt et al., 2007, Methods Enzymol.,435:221-45). While benefit may be achieved by administering PHDinhibitors before harvesting organs for transplant, administration of aninhibitor to the organ/tissue after harvest, either in storage (e.g.,cardioplegia solution) or post-transplant, may also be of therapeuticbenefit.

PHD inhibitors are expected to be effective in preserving tissue fromregional ischemia and/or hypoxia. This includes ischemia/hypoxiaassociated with inter alia: angina, myocardial ischemia, stroke,ischemia of skeletal muscle. There are a number of lines of experimentalevidence that support the concept that PHD inhibition and subsequentelevation of HIF as a useful method for preserving ischemic tissue.Recently, ischemic pre-conditioning has been demonstrated to be aHIF-dependent phenomenon (Cai et al., 2008, Cardiovasc Res.,77(3):463-70). Ischemic pre-conditioning is a well known phenomenonwhereby short periods of hypoxia and/or ischemia protect tissue fromsubsequent longer periods of ischemia (Murry et al., 1986, Circulation,74(5):1124-36; Das et al., 2008, IUBMB Life, 60(4):199-203). Ischemicpre-conditioning is known to occur in humans as well as experimentalanimals (Darling et al., 2007, Basic Res Cardiol., 102(3):274-8; KojimaI et al., 2007, J Am Soc Nephrol., 18:1218-26). While the concept ofpre-conditioning is best known for its protective effects in the heart,it also applies to other tissues including but not limited to: liver,skeletal muscle, liver, lung, kidney, intestine and brain (Pasupathy etal., 2005, Eur J Vasc Endovasc Surg., 29:106-15; Mallick et al., 2004,Dig Dis Sci., 49(9):1359-77). Experimental evidence for the tissueprotective effects of PHD inhibition and elevation of HIF have beenobtained in a number of animal models including: germ-line knock out ofPHD1 which conferred protection of the skeletal muscle from ischemicinsult (Aragonés et al., 2008, Nat Genet., 40(2):170-80), silencing ofPHD2 through the use of siRNA which protected the heart from ischemicinsult (Natarajan et al., 2006, Circ Res., 98(1):133-40), inhibition ofPHD by administering carbon monoxide which protected the myocardium fromischemic injury (Chin et al., 2007, Proc Natl Acad Sci. U.S.A.,104(12):5109-14), hypoxia in the brain which increased the tolerance toischemia (Bernaudin et al., 2002, J Cereb Blood Flow Metab.,22(4):393-403). In addition, small molecule inhibitors of PHD protectthe brain in experimental stroke models (Siddiq et al., 2005, J BiolChem., 280(50):41732-43). Moreover, HIF up-regulation has also beenshown to protect the heart of diabetic mice, where outcomes aregenerally worse (Natarajan et al., 2008, J Cardiovasc Pharmacol.,51(2):178-187). The tissue protective effects may also be observed inBuerger's disease, Raynaud's disease, and acrocyanosis.

The reduced reliance on aerobic metabolism via the Kreb's cycle in themitochondria and an increased reliance on anaerobic glycolysis producedby PHD inhibition may have beneficial effects in normoxic tissues. It isimportant to note that PHD inhibition has also been shown to elevate HIFunder normoxic conditions. Thus, PHD inhibition produces a pseudohypoxiaassociated with the hypoxic response being initiated through HIF butwith tissue oxygenation remaining normal. The alteration of metabolismproduced by PHD inhibition can also be expected to provide a treatmentparadigm for diabetes, obesity and related disorders, includingco-morbidities.

Globally, the collection of gene expression changes produced by PHDinhibition reduce the amount of energy generated per unit of glucose andwill stimulate the body to burn more fat to maintain energy balance. Themechanisms for the increase in glycolysis are discussed above. Otherobservations link the hypoxic response to effects that are expected tobe beneficial for the treatment of diabetes and obesity. Thus, highaltitude training is well known to reduce body fat (Armellini et al.,1997, Horm Metab Res., 29(9):458-61). Hypoxia and hypoxia mimetics suchas desferrioxamine have been shown to prevent adipocyte differentiation(Lin et al., 2006, J Biol Chem., 281(41):30678-83; Carrière et al.,2004, J Biol Chem., 279(39):40462-69). The effect is reversible uponreturning to normoxic conditions. Inhibition of PHD activity during theinitial stages of adipogenesis inhibits the formation of new adipocytes(Floyd et al., 2007, J Cell Biochem., 101:1545-57). Hypoxia, cobaltchloride and desferrioxamine elevated HIF and inhibited PPAR gamma 2nuclear hormone receptor transcription (Yun et al., 2002, Dev Cell.,2:331-41). As PPAR gamma 2 is an important signal for adipocytedifferentiation, PHD inhibition can be expected to inhibit adipocytedifferentiation. These effects were shown to be mediated by theHIF-regulated gene DEC1/Stra13 (Yun et al., supra).

Small molecular inhibitors of PHD have been demonstrated to havebeneficial effects in animal models of diabetes and obesity (Intl. Pat.Appl. Publ. WO2004/052284, Jun. 24, 2004; WO2004/052285, Jun. 24, 2004).Among the effects demonstrated for PHD inhibitors in mouse diet-inducedobesity, db/db mouse and Zucker fa/fa rat models were lowering of: bloodglucose concentration, fat mass in both abdominal and visceral fat pads,hemoglobin A1c, plasma triglycerides, body weight as well as changes inestablished disease bio-markers such as increases in the levels ofadrenomedullin and leptin. Leptin is a known HIF target gene product(Grosfeld et al., 2002, J Biol Chem., 277(45):42953-57). Gene productsinvolved in the metabolism in fat cells were demonstrated to beregulated by PHD inhibition in a HIF-dependent fashion (Intl. Pat. Appl.Publ. WO2004/052285, supra). These include apolipoprotein A-IV, acyl CoAthioesterase, carnitine acetyl transferase, and insulin-like growthfactor binding protein (IGFBP)-1.

PHD inhibitors are expected to be therapeutically useful as stimulantsof vasculogenesis, angiogenesis, and arteriogenesis. These processesestablish or restore blood flow and oxygenation to the tissues underischemia and/or hypoxia conditions (Semenza et al., 2007, J CellBiochem., 102:840-47; Semenza, 2007, Exp Physiol., 92(6):988-91). It hasbeen shown that physical exercise increases HIF-1 and vascularendothelial growth factor in experimental animal models and in humans(Gustafsson et al. 2001, Front Biosci., 6:D75-89) and consequently thenumber of blood vessels in skeletal muscle. VEGF is a well-known HIFtarget gene product that is a key driver of angiogenesis (Liu et al.,supra). While administration of various forms of VEGF receptoractivators are potent stimuli for angiogenesis, the blood vesselresulting from this potential form of therapy are leaky. This isconsidered to limit the potentially utility of VEGF for the treatment ofdisorders of oxygen delivery. The increased expression of a singleangiogenic factor may not be sufficient for functional vascularization(Semenza, 2007, supra). PHD inhibition offers a potential advantage overother such angiogenic therapies in that it stimulates a controlledexpression of multiple angiogenic growth factors in a HIF-dependentfashion including but not limited to: placental growth factor (PLGF),angiopoietin-1 (ANGPT1), angiopoietin-2 (ANGPT2), platelet-derivedgrowth factor beta (PDGFB) (Carmeliet, 2004, J Intern Med., 255:538-61;Kelly et al., 2003, Circ Res., 93:1074-81) and stromal cell derivedfactor 1 (SDF-1) (Ceradini et al., 2004, Nat Med., 10(8):858-64).Expression of angiopoietin-1 during angiogenesis producesleakage-resistant blood vessels, in contrast to the vessels produced byadministration of VEGF alone (Thurston et al., 1999, Science,286:2511-14; Thurston et al., 2000, Nat Med., 6(4):460-3; Elson et al.,2001, Genes Dev., 15(19):2520-32). Stromal cell derived factor 1 (SDF-1)has been shown to be critical to the process of recruiting endothelialprogenitor cells to the sites of tissue injury. SDF-1 expressionincreased the adhesion, migration and homing of circulatingCXCR4-positive progenitor cells to ischemic tissue. Furthermoreinhibition of SDF-1 in ischemic tissue or blockade of CXCR4 oncirculating cells prevents progenitor cell recruitment to sites ofinjury (Ceradini et al., 2004, supra; Ceradini et al., 2005, TrendsCardiovasc Med., 15(2):57-63). Importantly, the recruitment ofendothelial progenitor cells to sites of injury is reduced in aged miceand this is corrected by interventions that increase HIF at the woundsite (Chang et al., 2007, Circulation, 116(24):2818-29). PHD inhibitionoffers the advantage not only of increasing the expression of a numberof angiogenic factions but also a co-ordination in their expressionthroughout the angiogenesis process and recruitment of endothelialprogenitor cells to ischemic tissue.

Evidence for the utility of PHD inhibitors as pro-angiogenic therapiesis provided by the following observations. Adenovirus-mediatedover-expression of HIF has been demonstrated to induce angiogenesis innon-ischemic tissue of an adult animal (Kelly et al., 2003, Circ Res.,93(11):1074-81) providing evidence that therapies that elevate HIF, suchas PHD inhibition, will induce angiogenesis. Placental growth factor(PLGF), also a HIF target gene, has been show to play a critical role inangiogenesis in ischemic tissue (Carmeliet, 2004, J Intern Med.,255(5):538-61; Luttun et al., 2002, Ann N Y Acad Sci., 979:80-93). Thepotent pro-angiogenic effects of therapies that elevate HIF have beendemonstrated, via HIF over-expression, in skeletal muscle (Pajusola etal., 2005, FASEB J., 19(10):1365-7; Vincent et al., 2000, Circulation,102:2255-61) and in the myocardium (Shyu et al., 2002, Cardiovasc Res.,54:576-83). The recruitment of endothelial progenitor cells to theischemic myocardium by the HIF target gene SDF-1 has also beendemonstrated (Abbott et al., 2004, Circulation, 110(21):3300-05). Thesefindings support the general concept that PHD inhibitors will beeffective in stimulating angiogenesis in the setting of tissue ischemia,particularly muscle ischemia. It is expected that therapeuticangiogenesis produced by PHD inhibitors will be useful in restoringblood flow to tissues and therefore the treatment of disease includingbut not restricted to angina pectoris, myocardial ischemia andinfarction, peripheral ischemic disease, claudication, gastric andduodenal ulcers, ulcerative colitis, and inflammatory bowel disease.

PHD and HIF play a central role in tissue repair and regenerationincluding healing of wounds and ulcers. Recent studies have demonstratedthat an increased expression of all three PHDs at wound sites in agedmice with a resulting reduction in HIF accumulation (Chang et al.,supra). Thus, elevation of HIF in aged mice by administeringdesferrioxamine increased the degree of wound healing back to levelsobserved in young mice. Similarly, in a diabetic mouse model, HIFelevation was suppressed compared to non-diabetic litter mates (Mace etal., 2007, Wound Repair Regen., 15(5):636-45). Topical administration ofcobalt chloride, a hypoxia mimetic, or over-expression of a murine HIFthat lacks the oxygen-dependent degradation domain and thus provides fora constitutively active form of HIF, resulted in increased HIF at thewound site, increased expression of HIF target genes such as VEGF, Nos2,and Hmox1 and accelerated wound healing. The beneficial effect of PHDinhibition is not restricted to the skin and small molecule inhibitorsof PHD have recently been demonstrated to provide benefit in a mousemodel of colitis (Robinson et al., 2008, Gastroenterology,134(1):145-55).

PHD inhibition resulting in accumulation of HIF is expected to act by atleast four mechanisms to contribute to accelerated and more completehealing of wounds: 1) protection of tissue jeopardized by hypoxia and/orischemia, 2) stimulation of angiogenesis to establish or restoreappropriate blood flow to the site, 3) recruitment of endothelialprogenitor cells to wound sites, 4) stimulation of the release of growthfactors that specifically stimulate healing and regeneration.

Recombinant human platelet-derived growth factor (PDGF) is marketed asbecaplermin (Regranex™) and has been approved by the Food and DrugAdministration of the United States of America for “Treatment of lowerextremity diabetic neuropathic ulcers that extend into the subcutaneoustissue or beyond, and have adequate blood supply”. Becaplermin has beenshown to be effective in accelerating wound healing in diabetic patients(Steed, 2006, Plast Reconstr Surg., 117(7 Suppl):1435-1495; Nagai etal., 2002, Expert Opin Biol Ther., 2(2):211-8). As PDGF is a HIF genetarget (Schultz et al., 2006, Am J Physiol Heart Circ Physiol.,290(6):H2528-34; Yoshida et al., 2006, J Neurooncol., 76(1):13-21), PHDinhibition is expected to increase the expression of endogenous PDGF andproduce a similar or more beneficial effect to those produced withbecaplermin alone. Studies in animals have shown that topicalapplication of PDGF results in increased wound DNA, protein, andhydroxyproline amounts; formation of thicker granulation and epidermaltissue; and increased cellular repopulation of wound sites. PDGF exertsa local effect on enhancing the formation of new connective tissue. Theeffectiveness of PHD inhibition is expected to be greater than thatproduced by becaplermin due to the additional tissue protective andpro-angiogenic effects mediated by HIF.

The beneficial effects of inhibition of PHD are expected to extend notonly to accelerated wound healing in the skin and colon but also to thehealing of other tissue damage including but not limited togastrointestinal ulcers, skin graft replacements, burns, chronic woundsand frost bite.

Stem cells and progenitor cells are found in hypoxic niches within thebody and hypoxia regulates their differentiation and cell fate (Simon etal., 2008, Nat Rev Mol Cell Biol., 9:285-96). Thus PHD inhibitors may beuseful to maintain stem cells and progenitor cells in a pluripotentstate and to drive differentiation to desired cell types. Stem cells maybe useful in culturing and expanding stem cell populations and may holdcells in a pluripotent state while hormones and other factors areadministered to the cells to influence the differentiation and cellfate.

A further use of PHD inhibitors in the area of stem cell and progenitorcell therapeutics relates to the use of PHD inhibitors to conditionthese cells to withstand the process of implantation into the body andto generate an appropriate response to the body to make the stem celland progenitor cell implantation viable (Hu et al., 2008, J ThoracCardiovasc Surg., 135(4):799-808). More specifically PHD inhibitors mayfacilitate the integration of stem cells and draw in an appropriateblood supply to sustain the stem cells once they are integrated. Thisblood vessel formation will also function to carry hormones and otherfactors released from these cells to the rest of the body.

PHD inhibitors may also be useful in the treatment of infection(Peyssonnaux et al., 2005, J Invest Dermatol., 115(7):1806-15;Peyssonnaux et al., 2008 J Invest Dermatol., 2008 August;128(8):1964-8). HIF elevation has been demonstrated to increase theinnate immune response to infection in phagocytes and in keratinocytes.Phagocytes in which HIF is elevated show increased bacteriacidalactivity, increased nitric oxide production and increased expressed ofthe anti-bacterial peptide cathelicidin. These effects may also beuseful in treating infection from burns.

HIF has also been shown to be involved in bone growth and healing(Pfander D et al., 2003 J Cell Sci., 116(Pt 9):1819-26., Wang et al.,2007 J Clin Invest., 17(6):1616-26.) and may therefore be used to healor prevent fractures. HIF stimulates of glycolysis to provide energy toallow the synthesis of extracellular matrix of the epiphysealchondrocytes under a hypoxic environment. HIF also plays a role indriving the release of VEGF and angiogenesis in bone healing process.The growth of blood vessels into growing or healing bone can be the ratelimiting step in the process.

Certain small molecules with prolyl hydroxylase inhibitory activitieshave been described in the literature. These include, but are notlimited to, certain imidazo[1,2-a]pyridine derivatives (Warshakoon etal., 2006, Bioorg Med Chem Lett., 16(21):5598-601), substituted pyridinederivatives (Warshakoon et al., 2006, Bioorg Med Chem Lett.,16(21):5616-20), certain pyrazolopyridines (Warshakoon et al., 2006,Bioorg Med Chem Lett., 16(21):5687-90), certain bicyclic heteroaromaticN-substituted glycine derivatives (Intl. Pat. Appl. Publ. WO2007/103905,Sep. 13, 2007), quinoline based compounds (Intl. Pat. Appl. Publ.WO2007/070359, Jun. 21, 2007), certain pyrimidinetrione N-substitutedglycine derivatives (Intl. Pat. Appl. Publ. WO2007/150011, Dec. 27,2007), substituted aryl or heteroaryl amide compounds (U.S. Pat. Appl.Publ. No.: US 2007/0299086, Dec. 27, 2007) and substituted4-hydroxypyrimidine-5-carboxamides (Intl. Pat. Appl. Publ.WO2009/117269, Sep. 24, 2009).

However, there remains a need for potent prolyl hydroxylase modulatorswith desirable pharmaceutical properties. Certain aminoquinazolinylderivatives have been found in the context of this invention to haveprolyl hydroxylase modulating activity.

SUMMARY OF THE INVENTION

The present invention is directed to compounds which are usefulinhibitors of PHD. The compounds of the present invention are of generalFormula (I),

wherein:

-   n is 0-3-   R¹ is a member independently selected from the group consisting of    halo, —O—R^(c), —C₁₋₄alkyl, cyclohexyl, phenyl optionally    substituted with —C₁₋₄alkyl, benzyl optionally substituted with    —C₁₋₄alkyl, and —NR^(a)R^(b);-   R^(a) is H and R^(b) is benzyl optionally substituted with    —C₁₋₄alkyl, or R^(a) and R^(b) are taken together with the nitrogen    to which they are attached to form a piperidine ring;-   R^(c) is cyclohexyl, phenyl optionally substituted with one or more    R^(d) members;-   R^(d) is a member independently selected from the group consisting    of —H, halo, and —C₁₋₄alkyl;-   R² is a member independently selected from the group consisting of    —H, and —C₁₋₄alkyl,-   R³ is a member independently selected from the group consisting of    —H, —C₁₋₄alkyl optionally substituted with —OCH₃ or —N(C₁₋₄alkyl)₂,    cyano, —SO₂CH₃, tetrahydropyran, —(CH₂)_(m)C₃₋₈cycloalkyl,    —(CH₂)_(m)phenyl optionally substituted with one or more halo, or    —C₁₋₄alkyl;-   m is 0-1;-   R² and R³ can be taken together with the nitrogen to which they are    attached to form a 4 to 7 membered heterocycloalkyl ring optionally    containing O, N, S optionally substituted with —OH, cyano, halo,    —N—C(O)C₁₋₄alkyl, and —C₁₋₄alkyl;    and enantiomers, diastereomers, racemates, and pharmaceutically    acceptable salts thereof.

Isomeric forms of the compounds of formula (I), and of theirpharmaceutically acceptable salts, are encompassed within the presentinvention, and reference herein to one of such isomeric forms is meantto refer to at least one of such isomeric forms. One of ordinary skillin the art will recognize that compounds according to this invention mayexist, for example, in a single isomeric form whereas other compoundsmay exist in the form of a regioisomeric mixture.

The invention also relates to pharmaceutically acceptable salts,pharmaceutically acceptable prodrugs, and pharmaceutically activemetabolites of compounds of Formula (I). In certain preferredembodiments, the compound of Formula (I) is a compound selected fromthose species described or exemplified in the detailed descriptionbelow.

In a further general aspect, the invention relates to pharmaceuticalcompositions each comprising: (a) an effective amount of a compound ofFormula (I), or a pharmaceutically acceptable salt, pharmaceuticallyacceptable prodrug, or pharmaceutically active metabolite thereof; and(b) a pharmaceutically acceptable excipient.

In another general aspect, the invention is directed to a method oftreating a subject suffering from or diagnosed with a disease, disorder,or medical condition mediated by a prolyl hydroxylase enzyme activity,comprising administering to the subject in need of such treatment aneffective amount of a compound of Formula (I), or a pharmaceuticallyacceptable salt, pharmaceutically acceptable prodrug, orpharmaceutically active metabolite thereof.

In certain preferred embodiments of the inventive method, the disease,disorder, or medical condition is selected from: anemia, vasculardisorders, metabolic disorders, and wound healing.

Additional embodiments, features, and advantages of the invention willbe apparent from the following detailed description and through practiceof the invention.

DETAILED DESCRIPTION

The invention may be more fully appreciated by reference to thefollowing description, including the following glossary of terms and theconcluding examples. For the sake of brevity, the disclosures of thepublications, including patents, cited in this specification are hereinincorporated by reference.

As used herein, the terms “including”, “containing” and “comprising” areused herein in their open, non-limiting sense.

The term “alkyl” refers to a straight- or branched-chain alkyl grouphaving from 1 to 12 carbon atoms in the chain. Examples of alkyl groupsinclude methyl (Me, which also may be structurally depicted by thesymbol, “/”), ethyl (Et), n-propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl (tBu), pentyl, isopentyl, tert-pentyl, hexyl,isohexyl, and groups that in light of the ordinary skill in the art andthe teachings provided herein would be considered equivalent to any oneof the foregoing examples.

The term “alkenyl” refers to a straight- or branched-chain alkenyl grouphaving from 2 to 12 carbon atoms in the chain. (The double bond of thealkenyl group is formed by two sp² hybridized carbon atoms.)Illustrative alkenyl groups include prop-2-enyl, but-2-enyl, but-3-enyl,2-methylprop-2-enyl, hex-2-enyl, and the like.

The term “alkynyl” refers to a straight- or branched-chain alkynyl grouphaving from 2 to 12 carbon atoms in the chain. (The triple bond of thealkynyl group is formed by two sp hybridized carbon atoms.) Illustrativealkynyl groups include prop-2-ynyl, but-2-ynyl, but-3-ynyl,2-methylbut-2-ynyl, hex-2-ynyl, and the like.

The term “cycloalkyl” refers to a saturated or partially saturated,monocyclic, fused polycyclic, or spiro polycyclic carbocycle having from3 to 12 ring atoms per carbocycle. Illustrative examples of cycloalkylgroups include the following entities, in the form of properly bondedmoieties:

A “heterocycloalkyl” refers to a monocyclic ring structure that issaturated or partially saturated, monocyclic, fused polycyclic, and hasfrom 3 to 8 ring atoms per ring structure selected from carbon atoms andup to two heteroatoms selected from nitrogen, oxygen, and sulfur. Thering structure may optionally contain up to two oxo groups on sulfurring members. Illustrative entities, in the form of properly bondedmoieties, include:

The term “heteroaryl” refers to a monocyclic, fused bicyclic, or fusedpolycyclic aromatic heterocycle (ring structure having ring atomsselected from carbon atoms and up to four heteroatoms selected fromnitrogen, oxygen, and sulfur) having from 3 to 12 ring atoms perheterocycle. Illustrative examples of heteroaryl groups include thefollowing entities, in the form of properly bonded moieties:

Those skilled in the art will recognize that the species of cycloalkyl,heterocycloalkyl, and heteroaryl groups listed or illustrated above arenot exhaustive, and that additional species within the scope of thesedefined terms may also be selected.

The term “halogen” represents chlorine, fluorine, bromine or iodine. Theterm “halo” represents chloro, fluoro, bromo or iodo.

The term “substituted” means that the specified group or moiety bearsone or more substituents. The term “unsubstituted” means that thespecified group bears no substituents. The term “optionally substituted”means that the specified group is unsubstituted or substituted by one ormore substituents. Where the term “substituted” is used to describe astructural system, the substitution is meant to occur at anyvalency-allowed position on the system. In cases where a specifiedmoiety or group is not expressly noted as being optionally substitutedor substituted with any specified substituent, it is understood thatsuch a moiety or group is intended to be unsubstituted.

Any formula given herein is intended to represent compounds havingstructures depicted by the structural formula as well as certainvariations or forms. In particular, compounds of any formula givenherein may have asymmetric centers and therefore exist in differentenantiomeric forms. All optical isomers and stereoisomers of thecompounds of the general formula, and mixtures thereof, are consideredwithin the scope of the formula. Thus, any formula given herein isintended to represent a racemate, one or more enantiomeric forms, one ormore diastereomeric forms, one or more atropisomeric forms, and mixturesthereof. Furthermore, certain structures may exist as geometric isomers(i.e., cis and trans isomers), as tautomers, or as atropisomers.Additionally, any formula given herein is intended to embrace hydrates,solvates, and polymorphs of such compounds, and mixtures thereof.

Additionally, any formula given herein is intended to refer also tohydrates, solvates, and polymorphs of such compounds, and mixturesthereof, even if such forms are not listed explicitly. Certain compoundsof Formula (I) or pharmaceutically acceptable salts of compounds ofFormula (I) may be obtained as solvates. Solvates include those formedfrom the interaction or complexation of compounds of the invention withone or more solvents, either in solution or as a solid or crystallineform. In some embodiments, the solvent is water and then the solvatesare hydrates. In addition, certain crystalline forms of compounds ofFormula (I) or pharmaceutically acceptable salts of compounds of Formula(I) may be obtained as co-crystals. In certain embodiments of theinvention, compounds of Formula (I) were obtained in a crystalline form.In other embodiments, crystalline forms of compounds of Formula (I) werecubic in nature. In other embodiments, pharmaceutically acceptable saltsof compounds of Formula (I) were obtained in a crystalline form. Instill other embodiments, compounds of Formula (I) were obtained in oneof several polymorphic forms, as a mixture of crystalline forms, as apolymorphic form, or as an amorphous form. In other embodiments,compounds of Formula (I) convert in solution between one or morecrystalline forms and/or polymorphic forms.

To provide a more concise description, some of the quantitativeexpressions given herein are not qualified with the term “about”. It isunderstood that, whether the term “about” is used explicitly or not,every quantity given herein is meant to refer to the actual given value,and it is also meant to refer to the approximation to such given valuethat would reasonably be inferred based on the ordinary skill in theart, including equivalents and approximations due to the experimentaland/or measurement conditions for such given value. Whenever a yield isgiven as a percentage, such yield refers to a mass of the entity forwhich the yield is given with respect to the maximum amount of the sameentity that could be obtained under the particular stoichiometricconditions. Concentrations that are given as percentages refer to massratios, unless indicated differently.

Reference to a chemical entity herein stands for a reference to any oneof: (a) the actually recited form of such chemical entity, and (b) anyof the forms of such chemical entity in the medium in which the compoundis being considered when named. For example, reference herein to acompound such as R—COOH, encompasses reference to any one of, forexample, R—COOH_((s)), R—COOH_((sol)), and R—COO⁻ _((sol)). In thisexample, R—COOH_((s)) refers to the solid compound, as it could be forexample in a tablet or some other solid pharmaceutical composition orpreparation; R—COOH_((sol)) refers to the undissociated form of thecompound in a solvent; and R—COO⁻ _((sol)) refers to the dissociatedform of the compound in a solvent, such as the dissociated form of thecompound in an aqueous environment, whether such dissociated formderives from R—COOH, from a salt thereof, or from any other entity thatyields R—COO⁻ upon dissociation in the medium being considered. Inanother example, an expression such as “exposing an entity to compoundof formula R—COOH” refers to the exposure of such entity to the form, orforms, of the compound R—COOH that exists, or exist, in the medium inwhich such exposure takes place. In still another example, an expressionsuch as “reacting an entity with a compound of formula R—COOH” refers tothe reacting of (a) such entity in the chemically relevant form, orforms, of such entity that exists, or exist, in the medium in which suchreacting takes place, with (b) the chemically relevant form, or forms,of the compound R—COOH that exists, or exist, in the medium in whichsuch reacting takes place. In this regard, if such entity is for examplein an aqueous environment, it is understood that the compound R—COOH isin such same medium, and therefore the entity is being exposed tospecies such as R—COOH_((aq)) and/or R—COO⁻ _((aq)), where the subscript“(aq)” stands for “aqueous” according to its conventional meaning inchemistry and biochemistry. A carboxylic acid functional group has beenchosen in these nomenclature examples; this choice is not intended,however, as a limitation but it is merely an illustration. It isunderstood that analogous examples can be provided in terms of otherfunctional groups, including but not limited to hydroxyl, basic nitrogenmembers, such as those in amines, and any other group that interacts ortransforms according to known manners in the medium that contains thecompound. Such interactions and transformations include, but are notlimited to, dissociation, association, tautomerism, solvolysis,including hydrolysis, solvation, including hydration, protonation, anddeprotonation.

In another example, a zwitterionic compound is encompassed herein byreferring to a compound that is known to form a zwitterion, even if itis not explicitly named in its zwitterionic form. Terms such aszwitterion, zwitterions, and their synonyms zwitterionic compound(s) arestandard IUPAC-endorsed names that are well known and part of standardsets of defined scientific names. In this regard, the name zwitterion isassigned the name identification CHEBI:27369 by the Chemical Entities ofBiological Inerest (ChEBI) dictionary of molecular entities. Asgenerally well known, a zwitterion or zwitterionic compound is a neutralcompound that has formal unit charges of opposite sign. Sometimes thesecompounds are referred to by the term “inner salts”. Other sources referto these compounds as “dipolar ions”, although the latter term isregarded by still other sources as a misnomer. As a specific example,aminoethanoic acid (the amino acid glycine) has the formula H₂NCH₂COOH,and it exists in some media (in this case in neutral media) in the formof the zwitterion ⁺H₃NCH₂COO⁻. Zwitterions, zwitterionic compounds,inner salts and dipolar ions in the known and well established meaningsof these terms are within the scope of this invention, as would in anycase be so appreciated by those of ordinary skill in the art. Becausethere is no need to name each and every embodiment that would berecognized by those of ordinary skill in the art, no structures of thezwitterionic compounds that are associated with the compounds of thisinvention are given explicitly herein. They are, however, part of theembodiments of this invention. No further examples in this regard areprovided herein because the interactions and transformations in a givenmedium that lead to the various forms of a given compound are known byany one of ordinary skill in the art.

Any formula given herein is also intended to represent unlabeled formsas well as isotopically labeled forms of the compounds. Isotopicallylabeled compounds have structures depicted by the formulas given hereinexcept that one or more atoms are replaced by an atom having a selectedatomic mass or mass number. Examples of isotopes that can beincorporated into compounds of the invention include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and chlorine,such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, ³⁶Cl,¹²⁵I, respectively. Such isotopically labeled compounds are useful inmetabolic studies (preferably with ¹⁴C), reaction kinetic studies (with,for example ²H or ³H), detection or imaging techniques [such as positronemission tomography (PET) or single-photon emission computed tomography(SPECT)] including drug or substrate tissue distribution assays, or inradioactive treatment of patients. In particular, an ¹⁸F or ¹¹C labeledcompound may be particularly preferred for PET or SPECT studies.Further, substitution with heavier isotopes such as deuterium (i.e., ²H)may afford certain therapeutic advantages resulting from greatermetabolic stability, for example increased in vivo half-life or reduceddosage requirements. Isotopically labeled compounds of this inventionand prodrugs thereof can generally be prepared by carrying out theprocedures disclosed in the schemes or in the examples and preparationsdescribed below by substituting a readily available isotopically labeledreagent for a non-isotopically labeled reagent.

By way of a first example on substituent terminology, if substituent S¹_(example) is one of S₁ and S₂, and substituent S² _(example) is one ofS₃ and S₄, then these assignments refer to embodiments of this inventiongiven according to the choices S¹ _(example) is S₁ and S² _(example) isS₃; S¹ _(example) is S₁ and S² _(example) is S₄; S¹ _(example) is S₂ andS² _(example) is S₃; S¹ _(example) is S₂ and S² _(example) is S₄; andequivalents of each one of such choices. The shorter terminology “S¹_(example) is one of S₁ and S₂, and S² _(example) is one of S₃ and S₄”is accordingly used herein for the sake of brevity, but not by way oflimitation. The foregoing first example on substituent terminology,which is stated in generic terms, is meant to illustrate the varioussubstituent assignments described herein. The foregoing convention givenherein for substituents extends, when applicable, to members such as R¹,R², R³, A, X⁴, X⁵, X⁶, X⁷, R^(a), R^(b), R^(c), and R^(d) and any othergeneric substituent symbol used herein.

Furthermore, when more than one assignment is given for any member orsubstituent, embodiments of this invention comprise the variousgroupings that can be made from the listed assignments, takenindependently, and equivalents thereof. By way of a second example onsubstituent terminology, if it is herein described that substituentS_(example) is one of S₁, S₂, and S₃, this listing refers to embodimentsof this invention for which S_(example) is S₁; S_(example) is S₂;S_(example) is S₃; S_(example) is one of S₁ and S₂; S_(example) is oneof S₁ and S₃; S_(example) is one of S₂ and S₃; S_(example) is one of S₁,S₂ and S₃; and S_(example) is any equivalent of each one of thesechoices. The shorter terminology “S_(example) is one of S₁, S₂, and S₃”is accordingly used herein for the sake of brevity, but not by way oflimitation. The foregoing second example on substituent terminology,which is stated in generic terms, is meant to illustrate the varioussubstituent assignments described herein. The foregoing convention givenherein for substituents extends, when applicable, to members such as R¹,R², R³, A, X⁴, X⁵, X⁶, X⁷, R^(a), R^(b), R^(c) and R^(d) and any othergeneric substituent symbol used herein.

The nomenclature “C_(1-j)” with J>i, when applied herein to a class ofsubstituents, is meant to refer to embodiments of this invention forwhich each and every one of the number of carbon members, from i to Jincluding i and j, is independently realized. By way of example, theterm C₁₋₃ refers independently to embodiments that have one carbonmember (C₁), embodiments that have two carbon members (C₂), andembodiments that have three carbon members (C₃).

The term C_(n-m)alkyl refers to an aliphatic chain, whether straight orbranched, with a total number N of carbon members in the chain thatsatisfies n≦N≦m, with m>n.

Any disubstituent referred to herein is meant to encompass the variousattachment possibilities when more than one of such possibilities areallowed. For example, reference to disubstituent -A-B-, where A≠B,refers herein to such disubstituent with A attached to a firstsubstituted member and B attached to a second substituted member, and italso refers to such disubstituent with A attached to the secondsubstituted member and B attached to the first substituted member.

According to the foregoing interpretive considerations on assignmentsand nomenclature, it is understood that explicit reference herein to aset implies, where chemically meaningful and unless indicated otherwise,independent reference to embodiments of such set, and reference to eachand every one of the possible embodiments of subsets of the set referredto explicitly.

Chemical depictions are intended to portray the compound portionscontaining the orientations as written.

The present invention includes the use of compounds of Formula (I),

the use of compounds of Formula (I) and pharmaceutical compositionscontaining such compounds thereof to treat patients (humans or othermammals) with disorders related to the modulation of the prolylhydroxylase enzyme. The instant invention also includes methods ofmaking such a compound, pharmaceutical composition, pharmaceuticallyacceptable salt, pharmaceutically acceptable prodrug, andpharmaceutically active metabolites thereof.

In the present invention described by of Formula (I), where n is 0-3,and R¹ is independently bromo, chloro, fluoro, methyl, isopropyl,cyclohexyl, cyclohexyloxy, phenyl, 2-methylphenyl, benzyl, phenoxy,4-chlorophenoxy, 2,6-dimethyl-phenoxy, piperidinyl, and(2,6-dimethylbenzyl)amino.

In further preferred embodiments, n is 1.

In further preferred embodiments, n is 2.

In further preferred embodiments, n is 3.

In further preferred embodiments, R^(a) is —H and R^(b) is2,6-dimethylbenzyl.

In further preferred embodiments, R^(a) and R^(b) can be taken togetherwith the nitrogen to which they are attached to form a piperidine ring.

In further preferred embodiments, R^(c) can be phenyl, cyclohexyl,4-chlorophenyl, or 2,6-dimethyl-phenyl.

In further preferred embodiments, R^(d) can independently be —H, chloro,and —CH₃.

In further preferred embodiments, R² is —H and R³ can independently be—H, cyano, methyl, ethyl, propyl, tertbutyl, cyclopropyl,cyclopropylmethyl, tetrahydropyranyl, cyclohexylmethyl, phenyl,2-chlorophenyl, 2,6-dimethylbenzyl, and —SO₂CH₃.

In further preferred embodiments, R² can be methyl, ethyl, propyl, orbutyl.

In further preferred embodiments, R³ can be methyl, ethyl, propyl,butyl, tertbutyl, 2-methoxyethyl, 2-methoxy-1-methyl-ethyl ordiethylamino-ethyl.

In further preferred embodiments, R² and R³ can be taken together withthe nitrogen to which they are attached to form pyrrolidine, piperidine,4-methyl-1,4-diazepane, thiomorpholine, 4-hydroxypiperidine, morpholine,4-acetamidopiperidine, 4-cyanopiperidine, 4-fluoropiperidine, azepane,or 4-isopropylpiperidine.

In certain preferred embodiments, the compound of Formula (I) isselected from the group consisting of:

Ex. Chemical Name 11-[4-Amino-6-(2,6-dimethyl-phenoxy)-7-fluoro-quinazolin-2-yl]-1H-pyrazole-4-carboxylic acid; 21-[6-(2,6-Dimethyl-phenoxy)-7-fluoro-4-methylamino-quinazolin-2-yl]-1H-pyrazole-4-carboxylic acid; 31-[4-Dimethylamino-6-(2,6-dimethyl-phenoxy)-7-fluoro-quinazolin-2-yl]-1H-pyrazole-4-carboxylic acid; 41-[6-(2,6-Dimethyl-phenoxy)-7-fluoro-4-piperidin-1-yl-quinazolin-2-yl]-1H-pyrazole-4-carboxylic acid; 51-[6-(2,6-Dimethyl-phenoxy)-7-fluoro-4-pyrrolidin-1-yl-quinazolin-2-yl]-1H-pyrazole-4-carboxylic acid; 61-[6-(2,6-Dimethyl-phenoxy)-7-fluoro-4-phenylamino-quinazolin-2-yl]-1H-pyrazole-4-carboxylic acid; 71-[4-(2-Chloro-phenylamino)-6-(2,6-dimethyl-phenoxy)-7-fluoro-quinazolin-2-yl]-1H-pyrazole-4-carboxylic acid; 81-[6-(2,6-Dimethyl-phenoxy)-7-fluoro-4-propylamino-quinazolin-2-yl]-1H-pyrazole-4-carboxylic acid; 9(rac)-1-[6-(2,6-Dimethyl-phenoxy)-7-fluoro-4-(2-methoxy-1-methyl-ethylamino)-quinazolin-2-yl]-1H-pyrazole-4-carboxylic acid; 101-[4-(2-Diethylamino-ethylamino)-6-(2,6-dimethyl-phenoxy)-7-fluoro-quinazolin-2-yl]-1H-pyrazole-4-carboxylic acid; 111-[6-(2,6-Dimethyl-phenoxy)-4-dibutylamino-7-fluoro-quinazolin-2-yl]-1H-pyrazole-4-carboxylic acid; 121-[6-(2,6-Dimethyl-phenoxy)-4-dipropylamino-7-fluoro-quinazolin-2-yl]-1H-pyrazole-4-carboxylic acid; 131-(4-((Cyclohexylmethyl)amino)-6-(2,6-dimethylphenoxy)-7-fluoroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 141-((4-Cyclopropylamino)-6-(2,6-dimethylphenoxy)-7-fluoroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 151-((4-Cyclopropanemethylamino)-6-(2,6-dimethylphenoxy)-7-fluoroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 161-(6-(2,6-Dimethylphenoxy)-7-fluoro-4-((tetrahydro-2H-pyran-4-yl)amino)quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 171-(6-(2,6-Dimethylphenoxy)-7-fluoro-4-(4-methyl-1,4-diazepan-1-yl)quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 181-(6-(2,6-Dimethylphenoxy)-7-fluoro-4-thiomorpholinoquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 191-(6-(2,6-dimethylphenoxy)-7-fluoro-4-(4-hydroxypiperidin-1-yl)quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 201-(6-(2,6-Dimethylphenoxy)-7-fluoro-4-morpholinoquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 211-(4-(4-Acetamidopiperidin-1-yl)-6-(2,6-dimethylphenoxy)-7-fluoroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 221-(6-Cyclohexyl-4-methylamino-quinazolin-2-yl)-1H-pyrazole-4-carboxylicacid; 231-[6-Cyclohexyl-4-(2,6-dimethyl-benzylamino)-quinazolin-2-yl]-1H-pyrazole-4-carboxylic acid; 241-(4-Amino-6-cyclohexylquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;251-(6-Cyclohexyl-4-(pyrrolidin-1-yl)quinazolin-2-yl)-1H-pyrazole-4-carboxylicacid; 261-(6-Cyclohexyl-4-(piperidin-1-yl)quinazolin-2-yl)-1H-pyrazole-4-carboxylicacid; 271-(6-Cyclohexyl-4-(diethylamino)quinazolin-2-yl)-1H-pyrazole-4-carboxylicacid; 281-(6-Cyclohexyl-4-(phenylamino)quinazolin-2-yl)-1H-pyrazole-4-carboxylicacid; 291-(4-((2-Chlorophenyl)amino)-6-cyclohexylquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 301-(4-(4-Cyanopiperidin-1-yl)-6-cyclohexylquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 311-(6-Cyclohexyl-4-(4-fluoropiperidin-1-yl)quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 321-(6-Cyclohexyl-4-(cyclopropylamino)quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 331-(6-Cyclohexyl-4-morpholinoquinazolin-2-yl)-1H-pyrazole-4-carboxylicacid; 341-(6-Cyclohexyl-4-thiomorpholinoquinazolin-2-yl)-1H-pyrazole-4-carboxylicacid; 351-(4-Cyanamido-6-cyclohexylquinazolin-2-yl)-1H-pyrazole-4-carboxylicacid; 361-(4-(tert-Butylamino)-6-cyclohexylquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 371-(4-(Azepan-1-yl)-6-cyclohexylquinazolin-2-yl)-1H-pyrazole-4-carboxylicacid; 381-(6-Cyclohexyl-4-(dimethylamino)quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 391-(6-Cyclohexyl-4-((cyclohexylmethyl)amino)quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 401-(6-Cyclohexyl-4-(methylsulfonamido)quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 411-(4-(Dimethylamino)-6-phenylquinazolin-2-yl)-1H-pyrazole-4-carboxylicacid; 421-(4-(Ethyl(methyl)amino)-6-phenylquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 431-(6-Phenyl-4-(pyrrolidin-1-yl)quinazolin-2-yl)-1H-pyrazole-4-carboxylicacid; 441-(6-Phenyl-4-(phenylamino)quinazolin-2-yl)-1H-pyrazole-4-carboxylicacid 451-(6-Phenyl-4-(piperidin-1-yl)quinazolin-2-yl)-1H-pyrazole-4-carboxylicacid; 461-(4-(Diethylamino)-6-phenylquinazolin-2-yl)-1H-pyrazole-4-carboxylicacid; 471-(4-((2-Chlorophenyl)amino)-6-phenylquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 481-(4-(Azepan-1-yl)-6-phenylquinazolin-2-yl)-1H-pyrazole-4-carboxylicacid; 491-(4-((Cyclohexylmethyl)amino)-6-phenylquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 501-(4-Cyanamido-6-phenylquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;511-(4-(Cyclopropylamino)-6-phenylquinazolin-2-yl)-1H-pyrazole-4-carboxylicacid; 521-(4-(tert-Butylamino)-6-phenylquinazolin-2-yl)-1H-pyrazole-4-carboxylicacid; 53 1-(4-Amino-6-phenylquinazolin-2-yl)-1H-pyrazole-4-carboxylicacid; 541-(6-Phenyl-4-thiomorpholinoquinazolin-2-yl)-1H-pyrazole-4-carboxylicacid; 551-(4-(4-Acetamidopiperidin-1-yl)-6-phenylquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 561-(6-Phenyl-4-((tetrahydro-2H-pyran-4-yl)amino)quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 571-(4-(4-Methyl-1,4-diazepan-1-yl)-6-phenylquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 581-(4-Morpholino-6-phenylquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;59 1-(4-(4-Cyanopiperidin-1-yl)-6-phenylquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 601-(6-(4-Chlorophenoxy)-4-(diethylamino)quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 611-(6-(4-Chlorophenoxy)-4-(pyrrolidin-1-yl)quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 621-(6-(4-Chlorophenoxy)-4-(cyclopropylamino)quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 631-(6-(4-Chlorophenoxy)-4-(piperidin-1-yl)quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 641-(6-(4-Chlorophenoxy)-4-((cyclohexylmethyl)amino)quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 651-(6-(4-chlorophenoxy)-4-(4-cyanopiperidin-1-yl)quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 661-(4-(Azepan-1-yl)-6-(4-chlorophenoxy)quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 671-(6-(4-Chlorophenoxy)-4-thiomorpholinoquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 681-(6-(4-Chlorophenoxy)-4-((tetrahydro-2H-pyran-4-yl)amino)quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 691-(6-(4-Chlorophenoxy)-4-(phenylamino)quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 701-(4-(4-Acetamidopiperidin-1-yl)-6-(4-chlorophenoxy)quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 711-(6-(4-Chlorophenoxy)-4-(4-methyl-1,4-diazepan-1-yl)quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 721-(4-(tert-Butylamino)-6-phenoxyquinazolin-2-yl)-1H-pyrazole-4-carboxylicacid; 731-(6-Phenoxy-4-(pyrrolidin-1-yl)quinazolin-2-yl)-1H-pyrazole-4-carboxylicacid; 741-(4-(Diethylamino)-6-phenoxyquinazolin-2-yl)-1H-pyrazole-4-carboxylicacid; 751-(4-(Cyclopropylamino)-6-phenoxyquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 761-(6-Phenoxy-4-((tetrahydro-2H-pyran-4-yl)amino)quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 771-(4-(Dimethylamino)-7-phenoxyquinazolin-2-yl)-1H-pyrazole-4-carboxylicacid; 781-(7-Phenoxy-4-(pyrrolidin-1-yl)quinazolin-2-yl)-1H-pyrazole-4-carboxylicacid; 791-(7-Phenoxy-4-(piperidin-1-yl)quinazolin-2-yl)-1H-pyrazole-4-carboxylicacid; 801-(4-(Dimethylamino)-7-phenylquinazolin-2-yl)-1H-pyrazole-4-carboxylicacid; 811-(7-Phenyl-4-(pyrrolidin-1-yl)quinazolin-2-yl)-1H-pyrazole-4-carboxylicacid; 821-(7-Phenyl-4-(piperidin-1-yl)quinazolin-2-yl)-1H-pyrazole-4-carboxylicacid; 831-(4-(Diethylamino)-7-phenoxyquinazolin-2-yl)-1H-pyrazole-4-carboxylicacid; 841-(4-((Cyclohexylmethyl)amino)-7-phenoxyquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 851-(4-(4-Isopropylpiperidin-1-yl)-7-phenoxyquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 861-(4-(Cyclopropylamino)-7-phenoxyquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 871-(4-(Azepan-1-yl)-7-phenoxyquinazolin-2-yl)-1H-pyrazole-4-carboxylicacid; 881-(4-(Diethylamino)-6-(piperidin-1-yl)quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 891-(4-Morpholino-7-phenoxyquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;901-(7-Phenoxy-4-thiomorpholinoquinazolin-2-yl)-1H-pyrazole-4-carboxylicacid; 911-(4-(4-Fluoropiperidin-1-yl)-7-phenoxyquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 921-(4-(Dibutylamino)-7-phenoxyquinazolin-2-yl)-1H-pyrazole-4-carboxylicacid; 931-(4-(Dipropylamino)-7-phenoxyquinazolin-2-yl)-1H-pyrazole-4-carboxylicacid; 941-(4-(Ethyl(methyl)amino)-7-phenoxyquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 951-(4-((2-Methoxyethyl)(methyl)amino)-7-phenoxyquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 961-(7-Bromo-4-(diethylamino)quinazolin-2-yl)-1H-pyrazole-4-carboxylicacid; 97 1-(4-(Cyclohexylamino)-7-phenoxyquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 981-(4-((Cyclopropylmethyl)amino)-7-phenoxyquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 991-(4-(tert-Butylamino)-7-phenoxyquinazolin-2-yl)-1H-pyrazole-4-carboxylicacid. 1001-(6-(Cyclohexyloxy)-7-fluoro-4-morpholinoquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 1011-(6-(Cyclohexyloxy)-4-(dimethylamino)-7-fluoroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 1021-(6-(Cyclohexyloxy)-4-(diethylamino)-7-fluoroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 1031-(6-(Cyclohexyloxy)-7-fluoro-4-(pyrrolidin-1-yl)quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 1041-(6-(Cyclohexyloxy)-4-(ethyl(methyl)amino)-7-fluoroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 1051-(6-(Cyclohexyloxy)-4-(cyclopropylamino)-7-fluoroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 1061-(6-Benzyl-7-fluoro-4-morpholinoquinazolin-2-yl)-1H-pyrazole-4-carboxylicacid; 1071-(6-Benzyl-4-(dimethylamino)-7-fluoroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 1081-(6-Benzyl-4-(diethylamino)-7-fluoroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 1091-(6-Benzyl-7-fluoro-4-(pyrrolidin-1-yl)quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 1101-(6-Benzyl-4-(ethyl(methyl)amino)-7-fluoroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 1111-(6-Benzyl-4-(cyclopropylamino)-7-fluoroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 1121-(6-((2,6-Dimethylbenzyl)amino)-7-fluoro-4-morpholinoquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 1131-(4-(Dimethylamino)-6-((2,6-dimethylbenzyl)amino)-7-fluoroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 1141-(4-(Diethylamino)-6-((2,6-dimethylbenzyl)amino)-7-fluoroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;; 115 11-(6-((2,6-Dimethylbenzyl)amino)-7-fluoro-4-(pyrrolidin-1-yl)quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 1161-(6-((2,6-Dimethylbenzyl)amino)-4-(ethyl(methyl)amino)-7-fluoroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 1171-(4-(Cyclopropylamino)-6-((2,6-dimethylbenzyl)amino)-7-fluoroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 1181-(7-Fluoro-4-morpholino-6-(o-tolyl)quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 1191-(4-(Dimethylamino)-7-fluoro-6-(o-tolyl)quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 1201-(4-(Diethylamino)-7-fluoro-6-(o-tolyl)quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid 1211-(7-Fluoro-4-(pyrrolidin-1-yl)-6-(o-tolyl)quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 1221-(4-(Ethyl(methyl)amino)-7-fluoro-6-(o-tolyl)quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 1231-(4-(Cyclopropylamino)-7-fluoro-6-(o-tolyl)quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 1241-(7-Fluoro-6-isopropyl-4-morpholinoquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 1251-(4-(Dimethylamino)-7-fluoro-6-isopropylquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 1261-(4-(Diethylamino)-7-fluoro-6-isopropylquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 1271-(7-Fluoro-6-isopropyl-4-(pyrrolidin-1-yl)quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 1281-(4-(Ethyl(methyl)amino)-7-fluoro-6-isopropylquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 1291-(4-(Cyclopropylamino)-7-fluoro-6-isopropylquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 1301-(7-Fluoro-4-morpholino-6-(piperidin-1-yl)quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 1311-(4-(Dimethylamino)-7-fluoro-6-(piperidin-1-yl)quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 1321-(4-(Diethylamino)-7-fluoro-6-(piperidin-1-yl)quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 1331-(7-Fluoro-6-(piperidin-1-yl)-4-(pyrrolidin-1-yl)quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 1341-(4-(Ethyl(methyl)amino)-7-fluoro-6-(piperidin-1-yl)quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 1351-(4-(Cyclopropylamino)-7-fluoro-6-(piperidin-1-yl)quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 1361-(6-(Cyclohexyloxy)-7-chloro-4-morpholinoquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 1371-(6-(Cyclohexyloxy)-4-(dimethylamino)-7-chloroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 1381-(6-(Cyclohexyloxy)-4-(diethylamino)-7-chloroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 1391-(6-(Cyclohexyloxy)-7-chloro-4-(pyrrolidin-1-yl)quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 1401-(6-(Cyclohexyloxy)-4-(ethyl(methyl)amino)-7-chloroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 1411-(6-(Cyclohexyloxy)-4-(cyclopropylamino)-7-chloroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 1421-(6-Benzyl-7-chloro-4-morpholinoquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 1431-(6-Benzyl-4-(dimethylamino)-7-chloroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 1441-(6-Benzyl-4-(diethylamino)-7-chloroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 1451-(6-Benzyl-7-chloro-4-(pyrrolidin-1-yl)quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 1461-(6-Benzyl-4-(ethyl(methyl)amino)-7-chloroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 1471-(6-Benzyl-4-(cyclopropylamino)-7-chloroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 1481-(6-((2,6-Dimethylbenzyl)amino)-7-chloro-4-morpholinoquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 1491-(4-(Dimethylamino)-6-((2,6-dimethylbenzyl)amino)-7-chloroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;; 1501-(4-(Diethylamino)-6-((2,6-dimethylbenzyl)amino)-7-chloroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 1511-(6-((2,6-Dimethylbenzyl)amino)-7-chloro-4-(pyrrolidin-1-yl)quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 1521-(6-((2,6-Dimethylbenzyl)amino)-4-(ethyl(methyl)amino)-7-chloroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 1531-(4-(Cyclopropylamino)-6-((2,6-dimethylbenzyl)amino)-7-chloroquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 1541-(7-Chloro-4-morpholino-6-(o-tolyl)quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 1551-(4-(Dimethylamino)-7-chloro-6-(o-tolyl)quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 1561-(4-(Diethylamino)-7-chloro-6-(o-tolyl)quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 1571-(7-Chloro-4-(pyrrolidin-1-yl)-6-(o-tolyl)quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 1581-(4-(Ethyl(methyl)amino)-7-chloro-6-(o-tolyl)quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 1591-(4-(Cyclopropylamino)-7-chloro-6-(o-tolyl)quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 1601-(7-Chloro-6-isopropyl-4-morpholinoquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 1611-(4-(Dimethylamino)-7-chloro-6-isopropylquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 1621-(4-(Diethylamino)-7-chloro-6-isopropylquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 1631-(7-Chloro-6-isopropyl-4-(pyrrolidin-1-yl)quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 1641-(4-(Ethyl(methyl)amino)-7-chloro-6-isopropylquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 1651-(4-(Cyclopropylamino)-7-chloro-6-isopropylquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 1661-(7-Chloro-4-morpholino-6-(piperidin-1-yl)quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 1671-(4-(Dimethylamino)-7-chloro-6-(piperidin-1-yl)quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 1681-(4-(Diethylamino)-7-chloro-6-(piperidin-1-yl)quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 1691-(7-Chloro-6-(piperidin-1-yl)-4-(pyrrolidin-1-yl)quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 1701-(4-(Ethyl(methyl)amino)-7-chloro-6-(piperidin-1-yl)quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 1711-(4-(Cyclopropylamino)-7-chloro-6-(piperidin-1-yl)quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 1721-(6-(Cyclohexyloxy)-4-morpholinoquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 1731-(6-(Cyclohexyloxy)-4-(dimethylamino)quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 1741-(6-(Cyclohexyloxy)-4-(diethylamino)quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 1751-(6-(Cyclohexyloxy)-4-(pyrrolidin-1-yl)quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 1761-(6-(Cyclohexyloxy)-4-(cyclopropylamino)quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 1771-(6-(Cyclohexyloxy)-4-(ethyl(methyl)amino)quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 1781-(6-Benzyl-4-morpholinoquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;1791-(6-Benzyl-4-(dimethylamino)quinazolin-2-yl)-1H-pyrazole-4-carboxylicacid; 1801-(6-Benzyl-4-(diethylamino)quinazolin-2-yl)-1H-pyrazole-4-carboxylicacid; 1811-(6-Benzyl-4-(pyrrolidin-1-yl)quinazolin-2-yl)-1H-pyrazole-4-carboxylicacid; 1821-(6-Benzyl-4-(cyclopropylamino)quinazolin-2-yl)-1H-pyrazole-4-carboxylicacid; 1831-(6-Benzyl-4-(ethyl(methyl)amino)quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 1841-(6-Isopropyl-4-morpholinoquinazolin-2-yl)-1H-pyrazole-4-carboxylicacid; 1851-(6-Isopropyl-4-(dimethylamino)quinazolin-2-yl)-1H-pyrazole-4-carboxylicacid; 1861-(6-Isopropyl-4-(diethylamino)quinazolin-2-yl)-1H-pyrazole-4-carboxylicacid; 1871-(6-Isopropyl-4-(pyrrolidin-1-yl)quinazolin-2-yl)-1H-pyrazole-4-carboxylicacid; 1881-(6-Isopropyl-4-(cyclopropylamino)quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 1891-(6-Isopropyl-4-(ethyl(methyl)amino)quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 1901-(6-((2,6-Dimethylbenzyl)amino)-4-morpholinoquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 1911-(6-((2,6-Dimethylbenzyl)amino)-4-(dimethylamino)quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 1921-(6-((2,6-Dimethylbenzyl)amino)-4-(diethylamino)quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 1931-(6-((2,6-Dimethylbenzyl)amino)-4-(pyrrolidin-1-yl)quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 1941-(6-((2,6-Dimethylbenzyl)amino)-4-(cyclopropylamino)quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 1951-(6-((2,6-Dimethylbenzyl)amino)-4-(ethyl(methyl)amino)quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 1961-(4-Morpholino-6-(o-tolyl)quinazolin-2-yl)-1H-pyrazole-4-carboxylicacid; 1971-(4-(Dimethylamino)-6-(o-tolyl)quinazolin-2-yl)-1H-pyrazole-4-carboxylicacid; 1981-(4-(Diethylamino)-6-(o-tolyl)quinazolin-2-yl)-1H-pyrazole-4-carboxylicacid; 1991-(4-(Pyrrolidin-1-yl)-6-(o-tolyl)quinazolin-2-yl)-1H-pyrazole-4-carboxylicacid; 2001-(4-(Cyclopropylamino)-6-(o-tolyl)quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 2011-(4-(ethyl(methyl)amino)-6-(o-tolyl)quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 2021-(4-Morpholino-6-(piperidin-1-yl)quinazolin-2-yl)-1H-pyrazole-4-carboxylicacid; 2031-(4-(Dimethylamino)-6-(piperidin-1-yl)quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 2041-(4-(Diethylamino)-6-(piperidin-1-yl)quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 2051-(6-(Piperidin-1-yl)-4-(pyrrolidin-1-yl)quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 2061-(4-(Cyclopropylamino)-6-(piperidin-1-yl)quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 2071-(4-(Ethyl(methyl)amino)-6-(piperidin-1-yl)quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 2081-(6-(2,6-Dimethylphenoxy)-7-methyl-4-morpholinoquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 2091-(6-(2,6-Dimethylphenoxy)-7-methyl-4-dimethylaminoquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 2101-(6-(2,6-Dimethylphenoxy)-7-methyl-4-diethylaminoquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 2111-(6-(2,6-Dimethylphenoxy)-7-methyl-4-(pyrrolidin-1-yl)quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 2121-(6-(2,6-Dimethylphenoxy)-7-methyl-4-cyclopropylaminoquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 2131-(6-(2,6-Dimethylphenoxy)-4-(ethyl(methyl)amino)-7-methylquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid;and pharmaceutically acceptable salts thereof.

The invention includes also pharmaceutically acceptable salts of thecompounds of Formula (I), preferably of those described above and of thespecific compounds exemplified herein, and methods of treatment usingsuch salts.

A “pharmaceutically acceptable salt” is intended to mean a salt of afree acid or base of a compound represented by Formula (I) that isnon-toxic, biologically tolerable, or otherwise biologically suitablefor administration to the subject. See, generally, G. S. Paulekuhn, etal., “Trends in Active Pharmaceutical Ingredient Salt Selection based onAnalysis of the Orange Book Database”, J. Med. Chem., 2007, 50:6665-72,S. M. Berge, et al., “Pharmaceutical Salts”, J Pharm Sci., 1977,66:1-19, and Handbook of Pharmaceutical Salts, Properties, Selection,and Use, Stahl and Wermuth, Eds., Wiley-VCH and VHCA, Zurich, 2002.Examples of pharmaceutically acceptable salts are those that arepharmacologically effective and suitable for contact with the tissues ofpatients without undue toxicity, irritation, or allergic response. Acompound of Formula (I) may possess a sufficiently acidic group, asufficiently basic group, or both types of functional groups, andaccordingly react with a number of inorganic or organic bases, andinorganic and organic acids, to form a pharmaceutically acceptable salt.

Examples of pharmaceutically acceptable salts include sulfates,pyrosulfates, bisulfates, sulfites, bisulfites, phosphates,monohydrogen-phosphates, dihydrogenphosphates, metaphosphates,pyrophosphates, chlorides, bromides, iodides, acetates, propionates,decanoates, caprylates, acrylates, formates, isobutyrates, caproates,heptanoates, propiolates, oxalates, malonates, succinates, suberates,sebacates, fumarates, maleates, butyne-1,4-dioates, hexyne-1,6-dioates,benzoates, chlorobenzoates, methyl benzoates, dinitrobenzoates,hydroxybenzoates, methoxybenzoates, phthalates, sulfonates,xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates,citrates, lactates, γ-hydroxybutyrates, glycolates, tartrates,methane-sulfonates, propanesulfonates, naphthalene-1-sulfonates,naphthalene-2-sulfonates, and mandelates.

When the compound of Formula (I) contains a basic nitrogen, the desiredpharmaceutically acceptable salt may be prepared by any suitable methodavailable in the art, for example, treatment of the free base with aninorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuricacid, sulfamic acid, nitric acid, boric acid, phosphoric acid, and thelike, or with an organic acid, such as acetic acid, phenylacetic acid,propionic acid, stearic acid, lactic acid, ascorbic acid, maleic acid,hydroxymaleic acid, isethionic acid, succinic acid, valeric acid,fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid,salicylic acid, oleic acid, palmitic acid, lauric acid, a pyranosidylacid, such as glucuronic acid or galacturonic acid, an alpha-hydroxyacid, such as mandelic acid, citric acid, or tartaric acid, an aminoacid, such as aspartic acid, glutaric acid or glutamic acid, an aromaticacid, such as benzoic acid, 2-acetoxybenzoic acid, naphthoic acid, orcinnamic acid, a sulfonic acid, such as laurylsulfonic acid,p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, anycompatible mixture of acids such as those given as examples herein, andany other acid and mixture thereof that are regarded as equivalents oracceptable substitutes in light of the ordinary level of skill in thistechnology.

When the compound of Formula (I) is an acid, such as a carboxylic acidor sulfonic acid, the desired pharmaceutically acceptable salt may beprepared by any suitable method, for example, treatment of the free acidwith an inorganic or organic base, such as an amine (primary, secondaryor tertiary), an alkali metal hydroxide, alkaline earth metal hydroxide,any compatible mixture of bases such as those given as examples herein,and any other base and mixture thereof that are regarded as equivalentsor acceptable substitutes in light of the ordinary level of skill inthis technology. Illustrative examples of suitable salts include organicsalts derived from amino acids, such as N-methyl-D-glucamine, lysine,choline, glycine and arginine, ammonia, carbonates, bicarbonates,primary, secondary, and tertiary amines, and cyclic amines, such astromethamine, benzylamines, pyrrolidines, piperidine, morpholine, andpiperazine, and inorganic salts derived from sodium, calcium, potassium,magnesium, manganese, iron, copper, zinc, aluminum, and lithium.

Exemplary prodrugs include compounds having an amino acid residue, or apolypeptide chain of two or more (e.g., two, three or four) amino acidresidues, covalently joined through an amide or ester bond to a freeamino, hydroxy, or carboxylic acid group of a compound of Formula (I).Examples of amino acid residues include the twenty naturally occurringamino acids, commonly designated by three letter symbols, as well as4-hydroxyproline, hydroxylysine, demosine, isodemosine,3-methylhistidine, norvalin, beta-alanine, gamma-aminobutyric acid,citrulline homocysteine, homoserine, ornithine and methionine sulfone.

Additional types of prodrugs may be produced, for instance, byderivatizing free carboxyl groups of structures of Formula (I) as amidesor alkyl esters. Examples of amides include those derived from ammonia,primary C₁₋₆alkyl amines and secondary di(C₁₋₆alkyl) amines. Secondaryamines include 5- or 6-membered heterocycloalkyl or heteroaryl ringmoieties. Examples of amides include those that are derived fromammonia, C₁₋₃alkyl primary amines, and di(C₁₋₂alkyl)amines. Examples ofesters of the invention include C₁₋₇alkyl, C₅₋₇cycloalkyl, phenyl, andphenyl(C₁₋₆alkyl) esters. Preferred esters include methyl esters.Prodrugs may also be prepared by derivatizing free hydroxy groups usinggroups including hemisuccinates, phosphate esters,dimethylaminoacetates, and phosphoryloxymethyloxycarbonyls, followingprocedures such as those outlined in Fleisher et al., Adv. Drug DeliveryRev. 1996, 19, 115-130. Carbamate derivatives of hydroxy and aminogroups may also yield prodrugs. Carbonate derivatives, sulfonate esters,and sulfate esters of hydroxy groups may also provide prodrugs.Derivatization of hydroxy groups as (acyloxy)methyl and (acyloxy)ethylethers,

wherein the acyl group may be an alkyl ester, optionally substitutedwith one or more ether, amine, or carboxylic acid functionalities, orwhere the acyl group is an amino acid ester as described above, is alsouseful to yield prodrugs. Prodrugs of this type may be prepared asdescribed in Robinson et al., J Med Chem. 1996, 39 (1), 10-18. Freeamines can also be derivatized as amides, sulfonamides orphosphonamides. All of these prodrug moieties may incorporate groupsincluding ether, amine, and carboxylic acid functionalities.

The present invention also relates to pharmaceutically activemetabolites of the compounds of Formula (I), which may also be used inthe methods of the invention. A “pharmaceutically active metabolite”means a pharmacologically active product of metabolism in the body of acompound of Formula (I) or salt thereof. Prodrugs and active metabolitesof a compound may be determined using routine techniques known oravailable in the art. See, e.g., Bertolini, et al., J Med Chem. 1997,40, 2011-2016; Shan, et al., J Pharm Sci. 1997, 86 (7), 765-767;Bagshawe, Drug Dev Res. 1995, 34, 220-230; Bodor, Adv Drug Res. 1984,13, 224-331; Bundgaard, Design of Prodrugs (Elsevier Press, 1985); andLarsen, Design and Application of Prodrugs, Drug Design and Development(Krogsgaard-Larsen, et al., eds., Harwood Academic Publishers, 1991).

The compounds of Formula (I) and their pharmaceutically acceptablesalts, pharmaceutically acceptable prodrugs, and pharmaceutically activemetabolites of the present invention are useful as modulators of PHD inthe methods of the invention. “Modulators” include both inhibitors andactivators, where “inhibitors” refer to compounds that decrease,prevent, inactivate, desensitize or down-regulate PHD expression oractivity, and “activators” are compounds that increase, activate,facilitate, sensitize, or up-regulate PHD expression or activity.

The term “treat” or “treating” as used herein is intended to refer toadministration of an active agent or composition of the invention to asubject for the purpose of effecting a therapeutic or prophylacticbenefit through modulation of prolyl hydroxylase activity. Treatingincludes reversing, ameliorating, alleviating, inhibiting the progressof, lessening the severity of, or preventing a disease, disorder, orcondition, or one or more symptoms of such disease, disorder orcondition mediated through modulation of PHD activity. The term“subject” refers to a mammalian patient in need of such treatment, suchas a human.

Accordingly, the invention relates to methods of using the compoundsdescribed herein to treat subjects diagnosed with or suffering from adisease, disorder, or condition mediated by Prolyl Hydroxylase, such as:Anemia, vascular disorders, metabolic disorders, and wound healing.Symptoms or disease states are intended to be included within the scopeof “medical conditions, disorders, or diseases.”

As used herein the term “hypoxia” or “hypoxic disorder” refers to acondition where there is an insufficient level of oxygen provided in theblood or to tissues and organs. Hypoxic disorders can occur through avariety of mechanisms including where there is an insufficient capacityof the blood to carry oxygen (i.e. anemia), where there is an inadequateflow of blood to the tissue and/or organ caused by either heart failureor blockage of blood vessels and/or arteries (i.e. ischemia), wherethere is reduced barometric pressure (i.e. elevation sickness at highaltitudes), or where dysfunctional cells are unable to properly make useof oxygen (i.e. hystotoxic conditions). Accordingly, one of skill in theart would readily appreciate the present invention to be useful in thetreatment of a variety of hypoxic conditions including anemia, heartfailure, coronary artery disease, thromboembolism, stroke, angina andthe like.

In a preferred embodiment, molecules of the present invention are usefulin the treatment or prevention of anemia comprising treatment of anemicconditions associated with chronic kidney disease, polycystic kidneydisease, aplastic anemia, autoimmune hemolytic anemia, bone marrowtransplantation anemia, Churg-Strauss syndrome, Diamond Blackfan anemia,Fanconi's anemia, Felty syndrome, graft versus host disease,hematopoietic stem cell transplantation, hemolytic uremic syndrome,myelodysplastic syndrome, nocturnal paroxysmal hemoglobinuria,osteomyelofibrosis, pancytopenia, pure red-cell aplasia, purpuraSchoenlein-Henoch, refractory anemia with excess of blasts, rheumatoidarthritis, Shwachman syndrome, sickle cell disease, thalassemia major,thalassemia minor, thrombocytopenic purpura, anemic or non-anemicpatients undergoing surgery, anemia associated with or secondary totrauma, sideroblastic anemia, anemic secondary to other treatmentincluding: reverse transcriptase inhibitors to treat HIV, corticosteroidhormones, cyclic cisplatin or non-cisplatin-containingchemotherapeutics, vinca alkaloids, mitotic inhibitors, topoisomerase IIinhibitors, anthracyclines, alkylating agents, particularly anemiasecondary to inflammatory, aging and/or chronic diseases. PHD inhibitionmay also be used to treat symptoms of anemia including chronic fatigue,pallor and dizziness.

In another preferred embodiment, molecules of the present invention areuseful for the treatment or prevention of diseases of metabolicdisorders, including but not limited to diabetes and obesity. In anotherpreferred embodiment, molecules of the present invention are useful forthe treatment or prevention of vascular disorders. These include but arenot limited to hypoxic or wound healing related diseases requiringpro-angiogenic mediators for vasculogenesis, angiogenesis, andarteriogenesis

In treatment methods according to the invention, an effective amount ofa pharmaceutical agent according to the invention is administered to asubject suffering from or diagnosed as having such a disease, disorder,or condition. An “effective amount” means an amount or dose sufficientto generally bring about the desired therapeutic or prophylactic benefitin patients in need of such treatment for the designated disease,disorder, or condition. Effective amounts or doses of the compounds ofthe present invention may be ascertained by routine methods such asmodeling, dose escalation studies or clinical trials, and by taking intoconsideration routine factors, e.g., the mode or route of administrationor drug delivery, the pharmacokinetics of the compound, the severity andcourse of the disease, disorder, or condition, the subject's previous orongoing therapy, the subject's health status and response to drugs, andthe judgment of the treating physician. An example of a dose is in therange of from about 0.001 to about 200 mg of compound per kg ofsubject's body weight per day, preferably about 0.05 to 100 mg/kg/day,or about 1 to 35 mg/kg/day, in single or divided dosage units (e.g.,BID, TID, QID). For a 70-kg human, an illustrative range for a suitabledosage amount is from about 0.05 to about 7 g/day, or about 0.2 to about2.5 g/day.

Once improvement of the patient's disease, disorder, or condition hasoccurred, the dose may be adjusted for preventative or maintenancetreatment. For example, the dosage or the frequency of administration,or both, may be reduced as a function of the symptoms, to a level atwhich the desired therapeutic or prophylactic effect is maintained. Ofcourse, if symptoms have been alleviated to an appropriate level,treatment may cease. Patients may, however, require intermittenttreatment on a long-term basis upon any recurrence of symptoms.

In addition, the agents of the invention may be used in combination withadditional active ingredients in the treatment of the above conditions.The additional compounds may be co-administered separately with an agentof Formula (I) or included with such an agent as an additional activeingredient in a pharmaceutical composition according to the invention.In an exemplary embodiment, additional active ingredients are those thatare known or discovered to be effective in the treatment of conditions,disorders, or diseases mediated by PHD enzyme or that are active againstanother targets associated with the particular condition, disorder, ordisease, such as an alternate PHD modulator. The combination may serveto increase efficacy (e.g., by including in the combination a compoundpotentiating the potency or effectiveness of a compound according to theinvention), decrease one or more side effects, or decrease the requireddose of the compound according to the invention.

The compounds of the invention are used, alone or in combination withone or more other active ingredients, to formulate pharmaceuticalcompositions of the invention. A pharmaceutical composition of theinvention comprises: (a) an effective amount of a compound of Formula(I), or a pharmaceutically acceptable salt, pharmaceutically acceptableprodrug, or pharmaceutically active metabolite thereof; and (b) apharmaceutically acceptable excipient.

A “pharmaceutically acceptable excipient” refers to a substance that isnon-toxic, biologically tolerable, and otherwise biologically suitablefor administration to a subject, such as an inert substance, added to apharmacological composition or otherwise used as a vehicle, carrier, ordiluent to facilitate administration of a compound of the invention andthat is compatible therewith. Examples of excipients include calciumcarbonate, calcium phosphate, various sugars and types of starch,cellulose derivatives, gelatin, vegetable oils, and polyethyleneglycols.

Delivery forms of the pharmaceutical compositions containing one or moredosage units of the compounds of the invention may be prepared usingsuitable pharmaceutical excipients and compounding techniques now orlater known or available to those skilled in the art. The compositionsmay be administered in the inventive methods by oral, parenteral,rectal, topical, or ocular routes, or by inhalation.

The preparation may be in the form of tablets, capsules, sachets,dragees, powders, granules, lozenges, powders for reconstitution, liquidpreparations, or suppositories. Preferably, the compositions areformulated for intravenous infusion, topical administration, or oraladministration. A preferred mode of use of the invention is localadministration of PHD inhibitors particularly to sites where tissue hasbecome or has been made ischemic. This may be achieved via a specializedcatheter, angioplasty balloon or stent placement balloon.

For oral administration, the compounds of the invention can be providedin the form of tablets or capsules, or as a solution, emulsion, orsuspension. To prepare the oral compositions, the compounds may beformulated to yield a dosage of, e.g., from about 0.05 to about 100mg/kg daily, or from about 0.05 to about 35 mg/kg daily, or from about0.1 to about 10 mg/kg daily.

Oral tablets may include a compound according to the invention mixedwith pharmaceutically acceptable excipients such as inert diluents,disintegrating agents, binding agents, lubricating agents, sweeteningagents, flavoring agents, coloring agents and preservative agents.Suitable inert fillers include sodium and calcium carbonate, sodium andcalcium phosphate, lactose, starch, sugar, glucose, methyl cellulose,magnesium stearate, mannitol, sorbitol, and the like. Exemplary liquidoral excipients include ethanol, glycerol, water, and the like. Starch,polyvinyl-pyrrolidone (PVP), sodium starch glycolate, microcrystallinecellulose, and alginic acid are suitable disintegrating agents. Bindingagents may include starch and gelatin. The lubricating agent, ifpresent, may be magnesium stearate, stearic acid or talc. If desired,the tablets may be coated with a material such as glyceryl monostearateor glyceryl distearate to delay absorption in the gastrointestinaltract, or may be coated with an enteric coating.

Capsules for oral administration include hard and soft gelatin capsules.To prepare hard gelatin capsules, compounds of the invention may bemixed with a solid, semi-solid, or liquid diluent. Soft gelatin capsulesmay be prepared by mixing the compound of the invention with water, anoil such as peanut oil or olive oil, liquid paraffin, a mixture of monoand di-glycerides of short chain fatty acids, polyethylene glycol 400,or propylene glycol.

Liquids for oral administration may be in the form of suspensions,solutions, emulsions or syrups or may be presented as a dry product forreconstitution with water or other suitable vehicle before use. Suchliquid compositions may optionally contain: pharmaceutically-acceptableexcipients such as suspending agents (for example, sorbitol, methylcellulose, sodium alginate, gelatin, hydroxyethylcellulose,carboxymethylcellulose, aluminum stearate gel and the like); non-aqueousvehicles, e.g., oil (for example, almond oil or fractionated coconutoil), propylene glycol, ethyl alcohol, or water; preservatives (forexample, methyl or propyl p-hydroxybenzoate or sorbic acid); wettingagents such as lecithin; and, if desired, flavoring or coloring agents.

The active agents of this invention may also be administered by non-oralroutes. For example, the compositions may be formulated for rectaladministration as a suppository. For parenteral use, includingintravenous, intramuscular, intraperitoneal, or subcutaneous routes, thecompounds of the invention may be provided in sterile aqueous solutionsor suspensions, buffered to an appropriate pH and isotonicity or inparenterally acceptable oil. Suitable aqueous vehicles include Ringer'ssolution and isotonic sodium chloride. Such forms will be presented inunit-dose form such as ampules or disposable injection devices, inmulti-dose forms such as vials from which the appropriate dose may bewithdrawn, or in a solid form or pre-concentrate that can be used toprepare an injectable formulation. Illustrative infusion doses may rangefrom about 1 to 1000 μg/kg/minute of compound, admixed with apharmaceutical carrier over a period ranging from several minutes toseveral days.

For topical administration, the compounds may be mixed with apharmaceutical carrier at a concentration of about 0.1% to about 10% ofdrug to vehicle. Examples include lotions, creams, ointments and thelike and can be formulated by known methods. Another mode ofadministering the compounds of the invention may utilize a patchformulation to affect transdermal delivery.

Compounds of the invention may alternatively be administered in methodsof this invention by inhalation, via the nasal or oral routes, e.g., ina spray formulation also containing a suitable carrier.

Abbreviations and acronyms used herein including the following:

Term Acronym Diisopropylethylamine DIEA Tetrahydrofuran THFDichloromethane DCM Dimethyl Sulfoxide DMSO Dimethylacetamide DMAN,N-Dimethylformamide DMF Ethanol EtOH Acetonitrile ACN Ethyl AcetateEtOAc N-(3-Dimethylaminopropyl)-N- EDCI ethylcarbodiimideN,N′-Diisopropylcarbodiimide DIC Dichloroethane DCE

Exemplary compounds useful in methods of the invention will now bedescribed by reference to the illustrative synthetic schemes for theirgeneral preparation below and the specific examples that follow.Artisans will recognize that, to obtain the various compounds herein,starting materials may be suitably selected so that the ultimatelydesired substituents will be carried through the reaction scheme with orwithout protection as appropriate to yield the desired product.Alternatively, it may be necessary or desirable to employ, in the placeof the ultimately desired substituent, a suitable group that may becarried through the reaction scheme and replaced as appropriate with thedesired substituent. Unless otherwise specified, the variables are asdefined above in reference to Formula (I). Reactions may be performedbetween the melting point and the reflux temperature of the solvent, andpreferably between 0° C. and the reflux temperature of the solvent.Reactions may also be conducted in sealed pressure vessels above thenormal reflux temperature of the solvent.

Compounds of Formula (I) are prepared according to Scheme A fromappropriately substituted commercially available or syntheticallyaccessible anilines of formula (II) or (III), prepared using knownmethods, methods described in Scheme B, or methods as described in theJournal of Organic Chemistry, 2008, 73 (6), 2473-75. Referring to SchemeA, functionalized anilines of formula (II) or (III) are condensed withisothiocyanates such as ethyl isothiocyanatoformate in a solvent such asdichloromethane (DCM) at temperatures between room temperature and thereflux temperature of the solvent, to provide compounds of formula (IV).Subsequent coupling with commercially available substitutedpyrazole-4-carboxylates of formula (V), in the presence of a couplingreagent such as EDCI, DIC and the like, with or without an amine basesuch as triethylamine provides compounds of formula (VI). Cyclization ofcompounds of formula (VI) with an appropriate Lewis acid such aschlorotrimethylsilane, titanium (IV) chloride, and the like, in asolvent such as DCE or DMF, toluene and the like, at temperaturesbetween room temperature and the reflux temperature of the solvent,provides compounds of formula (VII). Treatment of compounds of theformula (VII) with an appropriate chlorinating agent such as POCl₃ inthe presence of a base such as DIEA in an appropriate solvent such asacetonitrile at temperatures between rt and reflux provide compounds ofthe formula (VIII). In certain cases it may be advantageous to addchloride ion from an appropriate source such as LiCl. Compounds of theformula (VIII) are treated with amines to afford compounds of theformula (IX). Saponification with a suitable base such as aq. NaOH, aq.LiOH or aq. KOH or a mixture thereof in a solvent such as THF attemperatures between rt and reflux provides compounds of Formula (I).There are an abundance of known and commercially available anilines thatmay be employed in the schemes herein. The schemes illustrated hereinalso provide guidance for synthesizing a variety of intermediates thatare not readily available and are useful for making compounds of thepresent invention

Ether intermediates of formula (II) are prepared according to Scheme B,where HAL is F, Cl. Commercially available appropriately substitutedhalo-nitro-benzenes of formula (X) are allowed to react with substitutedphenols (XI) in the presence of a base such as potassium carbonate, in asolvent such as DMSO, DMF, DMA, and the like, at temperatures betweenroom temperature and the reflux temperature of the solvent, providingnitro intermediates of formula (XII). Reduction of the nitro group,employing methods known to one skilled in the art, for example zincpowder in the presence of a saturated aqueous solution of NH₄Cl in asolvent such as acetone, and the like, affords aniline intermediates offormula (II).

Amino intermediates of formula (III) may be prepared similarly to themethods utilized for the ether intermediates as described above, byreplacing phenols with substituted alkyl amines, heterocycloalkyl aminesand aryl amines of formula (XIII).

EXAMPLES Chemistry

In obtaining the compounds described in the examples below and thecorresponding analytical data, the following experimental and analyticalprotocols were followed unless otherwise indicated.

Unless otherwise stated, reaction mixtures were magnetically stirred atroom temperature (rt). Where solutions were “dried,” they were generallydried over a drying agent such as Na₂SO₄ or MgSO₄. Where mixtures,solutions, and extracts were “concentrated”, they were typicallyconcentrated on a rotary evaporator under reduced pressure.

Thin-layer chromatography (TLC) was performed using Merck silica gel 60F₂₅₄ 2.5 cm×7.5 cm 250 μm or 5.0 cm×10.0 cm 250 μm pre-coated silica gelplates. Preparative thin-layer chromatography was performed using EMScience silica gel 60 F₂₅₄ 20 cm×20 cm 0.5 mm pre-coated plates with a20 cm×4 cm concentrating zone.

Normal-phase flash column chromatography (FCC) was performed on silicagel (SiO₂) eluting with hexanes/ethyl acetate, unless otherwise noted.

Reversed-phase HPLC was performed on a Hewlett Packard HPLC Series 1100,with a Phenomenex Luna C₁₈ (5 μm, 4.6×150 mm) column. Detection was doneat λ=230, 254 and 280 nm. The gradient was 10 to 99% acetonitrile/water(0.05% trifluoroacetic acid) over 5.0 min with a flow rate of 1 mL/min.Alternately, preparative HPLC purification was performed on a Gilsonautomated HPLC system running Gilson Unipoint LC software with uv peakdetection done at λ=220 nm and fitted with a reverse phase YMC-PackODS-A (5 μm, 30×250 mm) column; mobile gradient of 10-99% ofacetonitrile/water (0.05% trifluoroacetic acid) over 15-20 min and flowrates of 10-20 mL/min.

Mass spectra (MS) were obtained on an Agilent series 1100 MSD equippedwith a ESI/APCI positive and negative multimode source unless otherwiseindicated.

Nuclear magnetic resonance (NMR) spectra were obtained on Bruker modelDRX spectrometers. The format of the ¹H NMR data below is: chemicalshift in ppm downfield of the tetramethylsilane reference (apparentmultiplicity, coupling constant J in Hz, integration).

Chemical names were generated using ChemDraw Version 6.0.2(CambridgeSoft, Cambridge, Mass.) or ACD/Name Version 9 (AdvancedChemistry Development, Toronto, Ontario, Canada).

Example 11-[4-Amino-6-(2,6-dimethyl-phenoxy)-7-fluoro-quinazolin-2-yl]-1H-pyrazole-4-carboxylicacid

Step A: Preparation of 3-fluoro-4-(2,6-dimethyl-phenoxy)aniline. Solid2,6-dimethylphenol (42.4 g, 346 mmol) was added in portions to a stirredmixture of 3,4-difluoronitrobenzene (50.0 g, 314 mmol), K₂CO₃ (65.0 g,138 mmol), and DMSO (500 mL). After the addition was complete, themixture was heated to 80° C. for 8 h and then allowed to cool to rt. Themixture was poured into ice water, and the resulting precipitate wascollected and dried. This material was dissolved in acetone (1 L), then150 mL of saturated aqueous NH₄Cl was added and the mixture was immersedin an ice bath with mechanical stirring. Solid Zn powder (204 g, 65.4mmol) was added in portions at such a rate that the internal temperatureof the reaction mixture did not rise above 20° C. Following completionof the addition, the mixture was allowed to warm to rt and stirring wasmaintained for 6 h. EtOAc (ethyl acetate) (1.5 L) and anhydrous sodiumsulfate (500 g) were added, and stirring was continued for 30 min. Themixture was then filtered though a pad of Celite®, rinsing well withEtOAc, and the filtrate was concentrated. The residue was trituratedwith hexanes to afford a solid (64.5 g, 90%). ¹H NMR (400 MHz, CDCl₃):7.10-6.99 (m, 3H), 6.55 (ddd, J=12.5, 2.1, 0.8 Hz, 1H), 6.25-6.19 (m,2H), 3.50 (s, 2H), 2.15 (s, 6H).

Step B: Preparation of1-(4-(2,6-dimethylphenoxy)-3-fluorophenyl)-3-ethoxycarbonylthiourea. Amixture of 3-fluoro-4-(2,6-dimethyl-phenoxy)aniline (15.4 g, 66.6 mmol)and DCM (250 mL) was cooled in an ice bath, then neat ethylisocyanatoformate (9.61 g, 73.2 mmol) was added over 10 min. Theresulting solution was allowed to warm to rt and was maintained for 2 h.The solution was concentrated, and the residue was triturated with 50:50hexanes/ether, affording the titled compound as a solid (21.8 g, 90%).MS (ESI): mass calcd. for C₁₈H₁₉FN₂O₃S, 362.1; m/z found, 363.1 [M+H]⁺.

Step C: Preparation of1-(6-(2,6-dimethylphenoxy)-7-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylicacid, ethyl ester. Neat diisopropylcarbodiimide (45.4 g, 290 mmol) wasadded to a solution of1-(4-(2,6-dimethylphenoxy)-3-fluorophenyl)-3-ethoxycarbonylthiourea (100g, 276 mmol), ethyl pyrazole-4-carboxylate (45.4 g, 290 mmol), and DCM(1 L). The solution was maintained at rt for 24 h, then concentrated.The residue was stirred with ether (500 mL) for 3 h in an ice bath, thenfiltered. The filtrate was concentrated to a thick orange oil (180 g,ca. 70% purity, 97%). A portion of this material (20 g, ca. 30 mmol) wasdissolved in DCE (150 mL), then neat TiCl₄ was added. The mixture wasthen heated to reflux for 6 h, then cooled in an ice bath. EtOH (750 mL)was added, and the mixture was stirred for 3 h. The resultingprecipitate was collected by filtration, washed with cold EtOH, anddried to provide the titled compound (3.9 g, 31%). ¹H NMR (500 MHz,DMSO): 13.03 (s, 1H), 8.95 (d, J=0.6 Hz, 1H), 8.29 (s, 1H), 7.75 (d,J=11.5 Hz, 1H), 7.31-7.24 (m, 2H), 7.22 (dd, J=8.5, 6.4 Hz, 1H), 6.96(d, J=9.1 Hz, 1H), 4.29 (q, J=7.1 Hz, 2H), 2.11 (s, 6H), 1.32 (t, J=7.1Hz, 3H).

Step D: Preparation of1-[4-chloro-6-(2,6-dimethyl-phenoxy)-7-fluoro-quinazolin-2-yl]-1H-pyrazole-4-carboxylicacid, ethyl ester. A mixture of the above1-[6-(2,6-dimethyl-phenoxy)-7-fluoro-4-oxo-3,4-dihydro-quinazolin-2-yl]-1H-pyrazole-4-carboxylicacid ethyl ester (5.0 g, 12 mmol), LiCl (2.5 g, 59 mmol), POCl₃ (5.5 ml,59 mmol), DIEA (10 mL, 59 mmol), and acetonitrile (ACN) (50 mL) washeated to reflux for 6 h. The mixture was allowed to cool to rt and thenconcentrated. The residue was taken up in a minimal amount of DCM andpassed through a pad of silica gel, eluting with 50:50 hexanes/EtOAc.The resulting solution was concentrated to provide the titled compound.(5.2 g, >99%). ¹H NMR (500 MHz, DMSO-d₆): 9.13 (d, J=0.6 Hz, 1H), 8.23(d, J=0.6 Hz, 1H), 7.92 (d, J=10.7 Hz, 1H), 7.23-7.19 (m, 3H), 7.07 (d,J=8.6 Hz, 1H), 4.36 (q, J=7.1 Hz, 2H), 2.19 (s, 6H), 1.40 (t, J=7.1 Hz,3H).

Step E: Preparation of1-[4-amino-6-(2,6-dimethyl-phenoxy)-7-fluoro-quinazolin-2-yl]-1H-pyrazole-4-carboxylicacid, ethyl ester. A methanol solution of ammonia (7M, 0.39 mL, 2.7mmol) was added to a solution of the above1-[4-chloro-6-(2,6-dimethyl-phenoxy)-7-fluoro-quinazolin-2-yl]-1H-pyrazole-4-carboxylicacid, ethyl ester (120 mg, 0.27 mmol) and THF (2 mL). The mixture wasstirred 6 h, then concentrated. The residue was triturated with Et₂O,providing the titled compound (72 mg, 64%). ¹H NMR (500 MHz, DMSO-d₆):8.96 (d, J=0.8 Hz, 1H), 8.44-8.02 (m, 3H), 7.71 (d, J=11.9 Hz, 1H), 7.37(d, J=9.0 Hz, 1H), 7.24-7.20 (m, 2H), 7.17 (dd, J=8.6, 6.2 Hz, 1H), 4.27(q, J=7.1 Hz, 2H), 2.12 (s, 6H), 1.31 (t, J=7.1 Hz, 3H).

Step F: Preparation of1-[4-amino-6-(2,6-dimethyl-phenoxy)-7-fluoro-quinazolin-2-yl]-1H-pyrazole-4-carboxylicacid. A mixture of1-[4-amino-6-(2,6-dimethyl-phenoxy)-7-fluoro-quinazolin-2-yl]-1H-pyrazole-4-carboxylicacid, ethyl ester (65 mg, 0.15 mmol), 1M aqueous LiOH (1.5 mL, 1.5mmol), and THF (3 mL) was heated to 40° C. for 16 h with rapid stirring.The mixture was then cooled in an ice bath, and 1M HCl (1.5 mL, 1.5mmol) was added. The resulting precipitate was collected by filtration,washed with water, and dried to furnish the titled compound (45 mg,74%). MS (ESI): mass calcd. for C₂₀H₁₆FN₅O₃, 393.1; m/z found, 394.1[M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆): 12.72 (s, 1H), 8.91 (d, J=0.7 Hz,1H), 8.42-7.98 (m, 3H), 7.70 (d, J=11.9 Hz, 1H), 7.37 (d, J=9.0 Hz, 1H),7.25-7.20 (m, 2H), 7.17 (dd, J=8.6, 6.2 Hz, 1H), 2.12 (s, 6H).

Example 21-[6-(2,6-Dimethyl-phenoxy)-7-fluoro-4-methylamino-quinazolin-2-yl]-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 1,using methylamine in step E. MS (ESI): mass calcd. for C₂₁H₁₈FN₅O₃,407.1; m/z found, 408.1 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆): 12.76 (s,1H), 8.99 (d, J=0.7 Hz, 1H), 8.60 (d, J=4.5 Hz, 1H), 8.08 (d, J=0.7 Hz,1H), 7.71 (d, J=11.9 Hz, 1H), 7.34 (d, J=8.9 Hz, 1H), 7.27-7.22 (m, 2H),7.19 (dd, J=8.6, 6.2 Hz, 1H), 3.00 (d, J=4.5 Hz, 3H), 2.12 (s, 6H).

Example 31-[4-Dimethylamino-6-(2,6-dimethyl-phenoxy)-7-fluoro-quinazolin-2-yl]-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 1,using dimethylamine in step E. MS (ESI): mass calcd. for C₂₂H₂₀FN₅O₃,421.2; m/z found, 422.1 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆): 12.77 (s,1H), 8.97 (d, J=0.7 Hz, 1H), 8.09 (d, J=0.7 Hz, 1H), 7.79 (d, J=11.9 Hz,1H), 7.32-7.16 (m, 3H), 6.99 (d, J=9.1 Hz, 1H), 3.12 (s, 6H), 2.13 (s,6H).

Example 41-[6-(2,6-Dimethyl-phenoxy)-7-fluoro-4-piperidin-1-yl-quinazolin-2-yl]-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 1,using piperidine in step E. MS (ESI): mass calcd. for C₂₅H₂₄FN₅O₃,461.2; m/z found, 462.1 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆): 12.77 (s,1H), 8.96 (d, J=0.7 Hz, 1H), 8.09 (d, J=0.7 Hz, 1H), 7.83 (d, J=11.8 Hz,1H), 7.31-7.19 (m, 3H), 6.70 (d, J=9.1 Hz, 1H), 3.58-3.48 (m, 4H), 2.13(s, 6H), 1.66-1.53 (m, 2H), 1.47-1.35 (m, 4H).

Example 51-[6-(2,6-Dimethyl-phenoxy)-7-fluoro-4-pyrrolidin-1-yl-quinazolin-2-yl]-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 1,using pyrrolidine in step E. MS (ESI): mass calcd. for C₂₄H₂₂FN₅O₃,447.2; m/z found, 448.2 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆): 12.74 (s,1H), 8.95 (s, 1H), 8.08 (s, 1H), 7.75 (d, J=12.0 Hz, 1H), 7.30-7.12 (m,4H), 3.66-3.48 (m, 4H), 2.14 (s, 6H), 1.91-1.80 (m, 4H).

Example 61-[6-(2,6-Dimethyl-phenoxy)-7-fluoro-4-phenylamino-quinazolin-2-yl]-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 1,using aniline in step E with heating to 80° C. for 16 h. MS (ESI): masscalcd. for C₂₆H₂₀FN₅O₃, 469.2; m/z found, 470.1 [M+H]⁺. ¹H NMR (500 MHz,DMSO-d₆): 12.76 (s, 1H), 10.14 (s, 1H), 8.69 (d, J=0.7 Hz, 1H), 8.07 (d,J=0.7 Hz, 1H), 7.82 (d, J=11.8 Hz, 1H), 7.71-7.59 (m, 3H), 7.47-7.39 (m,2H), 7.28-7.15 (m, 4H), 2.16 (s, 6H).

Example 71-[4-(2-Chloro-phenylamino)-6-(2,6-dimethyl-phenoxy)-7-fluoro-quinazolin-2-yl]-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 1,using 2-chloroaniline in step E and heating to 80° C. for 16 h. MS(ESI): mass calcd. for C₂₆H₁₉ClFN₅O₃, 503.1; m/z found, 504.0 [M+H]⁺. ¹HNMR (500 MHz, DMSO-d₆): 12.72 (s, 1H), 10.30 (s, 1H), 8.42 (d, J=0.7 Hz,1H), 8.03 (d, J=0.7 Hz, 1H), 7.85 (d, J=11.8 Hz, 1H), 7.66-7.59 (m, 2H),7.54 (dd, J=7.8, 1.7 Hz, 1H), 7.48-7.38 (m, 2H), 7.28-7.23 (m, 2H), 7.19(dd, J=8.3, 6.6 Hz, 1H), 2.17 (s, 6H).

Example 81-[6-(2,6-Dimethyl-phenoxy)-7-fluoro-4-propylamino-quinazolin-2-yl]-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 1,using propylamine in step E. MS (ESI): mass calcd. for C₂₃H₂₂FN₅O₃,435.2; m/z found, 436.1 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆): 12.76 (s,1H), 8.94 (d, J=0.7 Hz, 1H), 8.67 (t, J=5.6 Hz, 1H), 8.09 (d, J=0.7 Hz,1H), 7.70 (d, J=11.9 Hz, 1H), 7.39 (d, J=8.9 Hz, 1H), 7.27-7.14 (m, 3H),3.49 (dd, J=14.0, 6.1 Hz, 2H), 2.12 (s, 6H), 1.71-1.57 (m, 2H), 0.90 (t,J=7.4 Hz, 3H).

Example 9(rac)-1-[6-(2,6-Dimethyl-phenoxy)-7-fluoro-4-(2-methoxy-1-methyl-ethylamino)-quinazolin-2-yl]-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 1,using racemic 2-methoxy-1-methylethylamine in step E. MS (ESI): masscalcd. for C₂₄H₂₄FN₅O₄, 465.2; m/z found, 467.1 [M+H]⁺. ¹H NMR (500 MHz,DMSO-d₆): 12.82 (s, 1H), 8.96 (d, J=0.7 Hz, 1H), 8.37 (d, J=7.9 Hz, 1H),8.09 (d, J=0.7 Hz, 1H), 7.67 (d, J=11.8 Hz, 1H), 7.54 (d, J=8.9 Hz, 1H),7.20-7.08 (m, 3H), 4.80-4.67 (m, 1H), 3.51 (dd, J=9.7, 6.5 Hz, 1H),3.44-3.35 (m, 1H, partially obstructed by water), 3.24 (d, J=3.3 Hz,3H), 2.11 (s, 6H), 1.21 (d, J=6.8 Hz, 3H).

Example 101-[4-(2-Diethylamino-ethylamino)-6-(2,6-dimethyl-phenoxy)-7-fluoro-quinazolin-2-yl]-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 1,using 2-dimethylaminoethylamine in step E. MS (ESI): mass calcd. forC₂₆H₂₉FN₆O₃, 492.2; m/z found, 493.5 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆):9.00 (s, 1H), 8.83 (s, 1H), 8.15 (s, 1H), 7.76 (d, J=11.8 Hz, 1H), 7.34(d, J=8.8 Hz, 1H), 7.27-7.14 (m, 3H), 3.71 (d, J=5.3 Hz, 2H), 3.08-2.84(m, 6H), 2.12 (s, 6H), 1.07 (t, J=7.0 Hz, 6H).

Example 111-[6-(2,6-Dimethyl-phenoxy)-4-dibutylamino-7-fluoro-quinazolin-2-yl]-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 1,using dibutylamine in step E. MS (ESI): mass calcd. for C₂₈H₃₂FN₅O₃,505.2; m/z found, 506.3 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆): 12.76 (s,1H), 8.87 (d, J=0.7 Hz, 1H), 8.09 (d, J=0.7 Hz, 1H), 7.79 (d, J=11.8 Hz,1H), 7.30-7.17 (m, 3H), 6.90 (d, J=9.0 Hz, 1H), 3.47-3.40 (m, 4H), 2.13(s, 6H), 1.52-1.37 (m, 4H), 1.15-1.03 (m, 4H), 0.85 (t, J=7.3 Hz, 6H).

Example 121-[6-(2,6-Dimethyl-phenoxy)-4-dipropylamino-7-fluoro-quinazolin-2-yl]-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 1,using dipropylamine in step E. MS (ESI): mass calcd. for C₂₆H₂₈FN₅O₃,477.2; m/z found, 478.4 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆): 12.77 (s,1H), 8.87 (d, J=0.6 Hz, 1H), 8.10 (d, J=0.6 Hz, 1H), 7.79 (d, J=11.8 Hz,1H), 7.30-7.24 (m, 2H), 7.20 (dd, J=8.4, 6.6 Hz, 1H), 6.88 (d, J=9.0 Hz,1H), 3.43-3.37 (m, 4H), 2.13 (s, 6H), 1.55-1.41 (m, 4H), 0.70 (t, J=7.4Hz, 6H).

Example 131-(4-((Cyclohexylmethyl)amino)-6-(2,6-dimethylphenoxy)-7-fluoroquinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 1,using cyclohexanemethylamine in step E. MS (ESI): mass calcd. forC₂₇H₂₈FN₅O₃, 490.1; m/z found, 489.2 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆):8.90 (d, J=0.6 Hz, 1H), 8.65 (t, J=5.7 Hz, 1H), 8.08 (d, J=0.6 Hz, 1H),7.68 (d, J=11.9 Hz, 1H), 7.43 (d, J 8.9 Hz, 1H), 7.25-7.14 (m, J=8.5,6.8 Hz, 3H), 3.39 (t, J=6.0 Hz, 2H), 2.12 (s, 6H), 1.73-1.53 (m, 6H),1.14 (t, J=9.4 Hz, 3H), 0.97 (t, J=11.6 Hz, 2H).

Example 141-((4-Cyclopropylamino)-6-(2,6-dimethylphenoxy)-7-fluoroquinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 1,using cycloproplyamine in step E. MS (ESI): mass calcd. for C₂₃H₂₀FN₅O₃,433.2; m/z found, 434.0 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆): 12.77 (s,1H), 9.00 (d, J=0.7 Hz, 1H), 8.72 (d, J=2.7 Hz, 1H), 8.10 (d, J=0.7 Hz,1H), 7.72 (d, J=11.8 Hz, 1H), 7.41 (d, J=8.9 Hz, 1H), 7.23-7.13 (m, 3H),3.04-2.93 (m, 1H), 2.11 (s, 6H), 0.88-0.76 (m, 2H), 0.68-0.57 (m, 2H).

Example 151-((4-Cyclopropanemethylamino)-6-(2,6-dimethylphenoxy)-7-fluoroquinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 1,using cyclopropanemethylamine in step E. MS (ESI): mass calcd. forC₂₄H₂₂FN₅O₃, 447.2; m/z found, 448.0 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆):12.75 (s, 1H), 8.95 (d, J=0.7 Hz, 1H), 8.76 (t, J=5.7 Hz, 1H), 8.09 (d,J=0.7 Hz, 1H), 7.71 (d, J=11.8 Hz, 1H), 7.39 (d, J=8.9 Hz, 1H),7.28-7.14 (m, J=8.5, 6.9 Hz, 3H), 3.43-3.38 (m, 2H), 2.13 (s, 6H),1.29-1.14 (m, 1H), 0.48-0.40 (m, 2H), 0.35-0.27 (m, 2H).

Example 161-(6-(2,6-Dimethylphenoxy)-7-fluoro-4-((tetrahydro-2H-pyran-4-yl)amino)quinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 1,using 4-aminotetrahydro-2H-pyran in step E. MS (ESI): mass calcd. forC₂₅H₂₄FN₅O₄, 477.2; m/z found, 478.0 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆):12.77 (s, 1H), 8.95 (d, J=0.5 Hz, 1H), 8.29 (d, J=7.5 Hz, 1H), 8.10 (d,J=0.5 Hz, 1H), 7.70 (d, J=11.8 Hz, 1H), 7.49 (d, J=8.9 Hz, 1H),7.24-7.12 (m, 3H), 4.55-4.39 (m, 1H), 3.91 (dd, J=11.0, 4.0 Hz, 2H),3.65-3.56 (m, 2H), 3.45 (t, J=11.1 Hz, 2H), 2.12 (s, 6H), 1.87 (dd,J=12.4, 2.6 Hz, 2H), 1.78-1.73 (m, 2H), 1.72-1.59 (m, 2H).

Example 171-(6-(2,6-Dimethylphenoxy)-7-fluoro-4-(4-methyl-1,4-diazepan-1-yl)quinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 1,using 4-methyl-1,4-diazepane) in step E. MS (ESI): mass calcd. forC₂₆H₂₇FN₆O₃, 490.2; m/z found, 491.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆):8.94 (s, 1H), 8.09 (d, J=0.4 Hz, 1H), 7.81 (d, J=11.9 Hz, 1H), 7.32-7.18(m, 3H), 6.89 (d, J=9.1 Hz, 1H), 3.84-3.73 (m, 2H), 3.66 (t, J=5.9 Hz,2H), 2.73-2.54 (m, 4H), 2.31 (s, 3H), 2.13 (s, 6H), 1.87-1.75 (m, 2H).

Example 181-(6-(2,6-Dimethylphenoxy)-7-fluoro-4-thiomorpholinoquinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 1,using thiomorpholine in step E. MS (ESI): mass calcd. for C₂₄H₂₂FN₅O₃S,479.1; m/z found, 480.0 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆): 12.79 (s,1H), 8.98 (d, J=0.7 Hz, 1H), 8.11 (d, J=0.7 Hz, 1H), 7.88 (d, J=11.8 Hz,1H), 7.33-7.21 (m, 3H), 6.65 (d, J=9.1 Hz, 1H), 3.86-3.75 (m, 4H),2.56-2.51 (m, 4H), 2.14 (s, 6H).

Example 191-(6-(2,6-Dimethylphenoxy)-7-fluoro-4-(4-hydroxypiperidin-1-yl)quinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 1,using 4-hydroxypiperidine in step E. MS (ESI): mass calcd. forC₂₅H₂₄FN₅O₃, 477.2; m/z found, 478.1 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆):12.78 (s, 1H), 8.96 (d, J=0.7 Hz, 1H), 8.10 (d, J=0.7 Hz, 1H), 7.84 (d,J=11.8 Hz, 1H), 7.32-7.19 (m, 3H), 6.71 (d, J=9.1 Hz, 1H), 4.81 (d,J=4.0 Hz, 1H), 3.87-3.66 (m, 3H), 3.32-3.24 (m, 2H), 1.73-1.61 (m, 2H),1.35-1.13 (m, 2H).

Example 201-(6-(2,6-Dimethylphenoxy)-7-fluoro-4-morpholinoquinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 1,using morpholine in step E. MS (ESI): mass calcd. for C₂₄H₂₂FN₅O₄,436.2; m/z found, 464.2 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆): 12.79 (s,1H), 9.00 (d, J=0.7 Hz, 1H), 8.11 (d, J=0.7 Hz, 1H), 7.89 (d, J=11.8 Hz,1H), 7.31-7.21 (m, 3H), 6.68 (d, J=9.1 Hz, 1H), 3.56 (s, 8H), 2.12 (s,6H).

Example 211-(4-(4-Acetamidopiperidin-1-yl)-6-(2,6-dimethylphenoxy)-7-fluoroquinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 1,using 4-acetamidopiperidine in step E. MS (ESI): mass calcd. forC₂₇H₂₇FN₆O₄, 518.2; m/z found, 519.1 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆):12.80 (s, 1H), 8.97 (d, J=0.7 Hz, 1H), 8.11 (d, J=0.7 Hz, 1H), 7.91-7.80(m, 2H), 7.32-7.19 (m, 3H), 6.70 (d, J=9.0 Hz, 1H), 3.96 (d, J=13.5 Hz,2H), 3.88-3.76 (m, 1H), 3.20 (t, J=11.1 Hz, 2H), 2.14 (s, 6H), 1.80 (s,3H), 1.75-1.66 (m, 2H), 1.34-1.20 (m, 2H).

Example 221-(6-Cyclohexyl-4-methylamino-quinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 1,Steps B-F using 4-cyclohexylaniline in step B and methylamine in step E.MS (ESI): mass calcd. for C₁₉H₂₁N₅O₂, 351.2; m/z found, 352.2 [M+H]⁺. ¹HNMR (500 MHz, DMSO-d₆): 12.74 (s, 1H), 9.04 (s, 1H), 8.78 (s, 1H), 8.10(s, 2H), 7.70 (d, J=8.6 Hz, 1H), 7.66 (d, J=8.4 Hz, 1H), 3.17-3.07 (m,3H), 2.65 (t, J=11.5 Hz, 1H), 1.95-1.80 (m, 4H), 1.75 (d, J=12.5 Hz,1H), 1.60-1.35 (m, 4H), 1.30-1.20 (m, 1H).

Example 231-[6-Cyclohexyl-4-(2,6-dimethyl-benzylamino)-quinazolin-2-yl]-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 1,Steps B-F using 4-cyclohexylaniline in step B and2,6-dimethylbenzylamine in step E. MS (ESI): mass calcd. for C₂₇H₂₉N₅O₂,455.2; m/z found, 456.2 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆): 12.72 (s,1H), 9.09 (s, 1H), 8.56 (s, 1H), 8.26 (s, 1H), 8.11 (s, 1H), 7.75-7.63(m, 2H), 7.20-7.13 (m, 1H), 7.13-7.06 (m, 2H), 4.87 (d, J=4.3 Hz, 2H),2.68-2.56 (m, 1H), 2.38 (s, 6H), 1.82 (t, J=12.0 Hz, 4H), 1.71 (d,J=12.9 Hz, 1H), 1.55-1.43 (m, 2H), 1.43-1.30 (m, 2H), 1.30-1.18 (m, 1H).

Example 241-(4-Amino-6-cyclohexylquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid

The titled compound was prepared in a manner analogous to EXAMPLE 1steps B through F using 4-cyclohexylaniline in step B and ammonia indioxane in step E. MS (ESI): mass calcd. for C₁₈H₁₉N₅O₂, 337.2; m/zfound, 338.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) 13.57-11.64 (m, 1H), 8.93(s, 1H), 8.59 (s, 2H), 8.17 (d, J=9.6 Hz, 2H), 7.75 (q, J=8.7 Hz, 2H),2.66 (t, J=11.7 Hz, 1H), 1.86 (t, J=12.7 Hz, 4H), 1.75 (d, J=12.2 Hz,1H), 1.59-1.34 (m, 4H), 1.34-1.21 (m, 1H).

Example 251-(6-Cyclohexyl-4-(pyrrolidin-1-yl)quinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 1steps B through F using 4-cyclohexylaniline in step B and pyrrolidine instep E. MS (ESI): mass calcd. for C₂₂H₂₅N₅O₂, 391.2; m/z found, 392.1[M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆): 12.80 (s, 1H), 9.04 (s, 1H), 8.17 (s,1H), 8.12 (s, 1H), 7.77 (s, 2H), 4.05 (s, 4H), 2.81-2.66 (m, 1H), 2.03(s, 4H), 1.92-1.79 (m, 4H), 1.73 (d, J=12.8 Hz, 1H), 1.58-1.35 (m, 4H),1.31-1.16 (m, 1H).

Example 261-(6-Cyclohexyl-4-(piperidin-1-yl)quinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 1steps B through F using 4-cyclohexylaniline in step B and piperidine instep E. MS (ESI): mass calcd. for C₂₃H₂₇N₅O₂, 405.2; m/z found, 406.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) 12.78-11.82 (m, 1H), 8.99 (s, 1H),8.10 (s, 1H), 7.75 (s, 2H), 7.73 (s, 1H), 3.85 (s, 4H), 2.69 (s, 1H),1.94-1.89 (m, 2H), 1.83-1.75 (m, 2H), 1.75 (s, 6H), 1.55-1.39 (m, 4H),1.34-1.28 (m, 2H).

Example 271-(6-Cyclohexyl-4-(diethylamino)quinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 1steps B through F using 4-cyclohexylaniline in step B and diethylaminein step E. MS (ESI): mass calcd. for C₂₂H₂₇N₅O₂, 393.2; m/z found, 394.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): 12.76 (s, 1H), 8.94 (s, 1H), 8.10 (s,1H), 7.80 (s, 1H), 7.73 (s, 1H), 7.72 (s, 1H), 3.82 (q, J=6.9 Hz, 4H),2.67 (s, 1H), 1.91 (s, 2H), 1.84 (s, 2H), 1.74 (d, J=12.1 Hz, 1H),1.51-1.35 (m, 11H).

Example 281-(6-Cyclohexyl-4-(phenylamino)quinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 1steps B through F using 4-cyclohexylaniline in step B and aniline instep E. MS (ESI): mass calcd. for C₂₄H₂₃N₅O₂, 413.2; m/z found, 414.3[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): 12.79 (s, 1H), 10.22 (s, 1H), 8.82(s, 1H), 8.45 (s, 1H), 8.13 (s, 1H), 7.91 (d, J=7.6 Hz, 2H), 7.81 (d,J=8.6 Hz, 1H), 7.76 (d, J=8.5 Hz, 1H), 7.52-7.45 (m, 2H), 7.23 (t, J=7.4Hz, 1H), 3.65-3.56 (m, 1H), 2.72 (t, J=11.8 Hz, 1H), 1.96-1.83 (m, 4H),1.82-1.72 (m, 2H), 1.66-1.52 (m, 2H), 1.44-1.32 (m, 2H), 1.30-1.23 (m,1H).

Example 291-(4-((2-Chlorophenyl)amino)-6-cyclohexylquinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 1steps B through F using 4-cyclohexylaniline in step B and2-chloroaniline in step E. MS (ESI): mass calcd. for C₂₄H₂₂ClN₅O₂,447.2; m/z found, 448.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): 10.35 (s,1H), 8.50 (s, 1H), 8.42 (s, 1H), 8.04 (s, 1H), 7.83 (dd, J=8.7, 1.7 Hz,1H), 7.76 (d, J=8.6 Hz, 1H), 7.69 (dd, J=4.0, 1.6 Hz, 1H), 7.67 (dd,J=3.9, 1.6 Hz, 1H), 7.51 (td, J=7.6, 1.5 Hz, 1H), 7.43 (td, J=7.7, 1.7Hz, 1H), 2.83-2.64 (m, 1H), 1.94 (d, J=11.8 Hz, 2H), 1.87 (d, J=12.7 Hz,2H), 1.79-1.73 (m, 1H), 1.68-1.51 (m, 2H), 1.51-1.36 (m, 2H), 1.36-1.22(m, 1H).

Example 301-(4-(4-Cyanopiperidin-1-yl)-6-cyclohexylquinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 1steps B through F using 4-cyclohexylaniline in step B and4-cyanopiperidine in step E. MS (ESI): mass calcd. for C₂₄H₂₆N₆O₂,430.2; m/z found, 431.1 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆): 12.78 (s,1H), 9.02 (s, 1H), 8.11 (s, 1H), 7.78 (s, 2H), 7.75 (s, 1H), 4.16-4.09(m, 2H), 3.75-3.64 (m, 2H), 3.30-3.20 (m, 1H), 2.89-2.73 (m, 1H),2.27-2.14 (m, 2H), 2.01-1.91 (m, 2H), 1.88 (d, J=12.3 Hz, 2H), 1.84 (d,J=12.4 Hz, 2H), 1.74 (d, J=12.6 Hz, 1H), 1.57-1.36 (m, 5H), 1.35-1.23(m, 1H).

Example 311-(6-Cyclohexyl-4-(4-fluoropiperidin-1-yl)quinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 1steps B through F using 4-cyclohexylaniline in step B and4-fluoropiperidine in step E. MS (ESI): mass calcd. for C₂₃H₂₆FN₅O₂,423.2; m/z found, 424.1 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆): 12.78 (s,1H), 9.01 (s, 1H), 8.11 (s, 1H), 7.78 (s, 3H), 5.19-4.93 (m, 1H),3.92-3.79 (m, 4H), 2.72-2.64 (m, 1H), 2.23-2.08 (m, 2H), 2.03-1.92 (m,2H), 1.89 (d, J=12.7 Hz, 2H), 1.83 (d, J=12.5 Hz, 2H), 1.74 (d, J=12.7Hz, 1H), 1.52-1.39 (m, 4H), 1.33-1.22 (m, 1H).

Example 321-(6-Cyclohexyl-4-(cyclopropylamino)quinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 1steps B through F using 4-cyclohexylaniline in step B andcyclopropylamine in step E. MS (ESI): mass calcd. for O₂₁H₂₃N₅O₂, 377.1;m/z found, 378.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): 9.33 (5, 1H), 9.14(5, 1H), 8.26 (5, 1H), 8.25 (5, 1H), 7.83-7.73 (m, 2H), 2.81-2.65 (m,1H), 1.84 (d, J=8.0 Hz, 4H), 1.74-1.62 (m, 1H), 1.52-1.48 (m, 2H),1.46-1.33 (m, 2H), 1.26-1.14 (m, 1H), 0.98-0.88 (m, 2H), 0.88-0.80 (m,2H).

Example 331-(6-Cyclohexyl-4-morpholinoquinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 1steps B through F using 4-cyclohexylaniline in step B and morpholine instep E. MS (ESI): mass calcd. for C₂₂H₂₅N₅O₃, 407.2; m/z found, 408.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): 12.79 (s, 1H), 9.03 (s, 1H), 8.12 (s,1H), 7.79 (5, 1H), 7.78 (5, 2H), 4.02-3.92 (m, 4H), 3.82 (d, J=4.3 Hz,4H), 2.73-2.64 (m, 1H), 1.92-1.85 (m, 4H), 1.73-1.68 (m, 1H), 1.53-1.38(m, 4H), 1.34-1.21 (m, 1H).

Example 341-(6-Cyclohexyl-4-thiomorpholinoquinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 1steps B through F using 4-cyclohexylaniline in step B and thiomorpholinein step E. MS (ESI): mass calcd. for C₂₂H₂₅N₅O₂S, 423.1; m/z found,424.1 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆): 12.80 (s, 1H), 9.01 (s, 1H),8.11 (s, 1H), 7.78 (s, 2H), 7.73 (s, 1H), 4.19-4.12 (m, 4H), 2.98-2.87(m, 4H), 2.72-2.64 (m, 1H), 2.06-1.89 (m, 2H), 1.88-1.82 (m, 2H),1.76-1.70 (m, 1H), 1.52-1.39 (m, 4H), 1.29-1.14 (m, 1H).

Example 351-(4-Cyanamido-6-cyclohexylquinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 1steps B through F using 4-cyclohexylaniline in step B and sodiumcyanamide in step E. MS (ESI): mass calcd. for C₁₉H₁₈N₆O₂, 362.1; m/zfound, 363.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): 13.19 (s, 1H), 8.89 (s,1H), 8.43 (s, 1H), 7.97 (s, 1H), 7.87 (d, J=8.6 Hz, 1H), 7.79 (d, J=8.6Hz, 1H), 2.66 (s, 1H), 1.82 (s, 4H), 1.72-1.68 (m, 1H), 1.42-1.30 (m,4H), 1.26-1.19 (m, 1H).

Example 361-(4-(tert-Butylamino)-6-cyclohexylquinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 1steps B through F using 4-cyclohexylaniline in step B andtert-butylamine in step E. MS (ESI): mass calcd. for C₂₂H₂₇N₅O₂, 393.2;m/z found, 394.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): 13.27-12.44 (m, 1H),8.89 (s, 1H), 8.29 (s, 1H), 8.18 (s, 1H), 7.94 (s, 1H), 7.76-7.71 (m,1H), 7.69 (d, J=8.6 Hz, 1H), 2.67 (t, J=11.8 Hz, 1H), 1.85 (d, J=10.5Hz, 4H), 1.75 (d, J=12.4 Hz, 1H), 1.63 (s, 9H), 1.59-1.50 (m, 2H),1.48-1.38 (m, 2H), 1.35-1.24 (m, 1H).

Example 371-(4-(Azepan-1-yl)-6-cyclohexylquinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 1steps B through F using 4-cyclohexylaniline in step B and homopiperidinein step E. MS (ESI): mass calcd. for C₂₄H₂₉N₅O₂, 419.2; m/z found, 420.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): 12.76 (s, 1H), 8.95 (s, 1H), 8.09 (s,1H), 7.92 (s, 1H), 7.74-7.69 (m, 2H), 4.08-3.96 (m, 4H), 2.68 (s, 1H),1.98 (s, 4H), 1.89 (d, J=10.5 Hz, 2H), 1.83 (d, J=12.0 Hz, 2H), 1.73 (d,J=11.9 Hz, 1H), 1.61 (s, 4H), 1.57-1.44 (m, 4H), 1.27 (d, J=12.2 Hz,1H).

Example 381-(6-Cyclohexyl-4-(dimethylamino)quinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 1steps B through F using 4-cyclohexylaniline in step B and dimethylaminein step E. MS (ESI): mass calcd. for C₂₀H₂₃N₅O₂, 365.2; m/z found, 366.2[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): 13.57-11.86 (m, 1H), 9.11 (s, 1H),8.24 (s, 1H), 8.05 (s, 1H), 7.82 (q, J=8.8 Hz, 2H), 3.54 (s, 6H), 2.73(t, J=11.5 Hz, 1H), 1.85 (t, J=12.7 Hz, 4H), 1.73 (d, J=11.6 Hz, 1H),1.57-1.44 (m, 4H), 1.34-1.20 (m, 1H).

Example 391-(6-Cyclohexyl-4-((cyclohexylmethyl)amino)quinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 1steps B through F using 4-cyclohexylaniline in step B andcyclohexylmethylamine in step E. MS (ESI): mass calcd. for C₂₅H₃₁N₅O₂,433.2; m/z found, 434.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): 12.76 (s,1H), 8.95 (s, 1H), 8.09 (s, 1H), 7.92 (5, 1H), 7.74-7.69 (m, 2H),4.08-3.96 (m, 4H), 2.68 (s, 1H), 1.98 (s, 4H), 1.89 (d, J=10.5 Hz, 2H),1.83 (d, J=12.0 Hz, 2H), 1.73 (d, J=11.9 Hz, 1H), 1.61 (s, 4H),1.44-1.31 (m, 4H), 1.27 (d, J=12.2 Hz, 1H).

Example 401-(6-Cyclohexyl-4-(methylsulfonamido)quinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 1steps B through F using 4-cyclohexylaniline in step B andmethanesulfonamide in step E. MS (ESI): mass calcd. for C₁₉H₂₁N₅O₄S,415.1; m/z found, 416.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): 12.88 (s,1H), 8.93 (s, 1H), 8.32 (s, 1H), 8.26 (s, 1H), 7.91-7.81 (m, 2H), 3.65(s, 3H), 2.70 (t, J=11.6 Hz, 1H), 1.87 (t, J=14.8 Hz, 4H), 1.79-1.70 (m,1H), 1.59-1.34 (m, 5H), 1.28-1.12 (m, 1H).

Example 411-(4-(Dimethylamino)-6-phenylquinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 1steps B through F using 4-phenylaniline in step B and dimethylamine instep E. MS (ESI): mass calcd. for C₂₀H₁₇N₅O₂, 359.1; m/z found, 360.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): 9.11 (s, 1H), 8.45 (s, 1H), 8.21 (s,1H), 8.18 (d, J=8.7, 1H), 7.94 (d, J=8.7 Hz, 1H), 7.81 (d, J=7.7 Hz,2H), 7.53 (t, J=7.7 Hz, 2H), 7.43 (t, J=7.3 Hz, 1H), 3.59 (s, 6H).

Example 421-(4-(Ethyl(methyl)amino)-6-phenylquinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 1steps B through F using 4-phenylaniline in step B and N-methylethylaminein step E. MS (ESI): mass calcd. for C₂₁H₁₉N₅O₂, 373.1; m/z found, 374.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): 13.24-12.33 (m, 1H), 9.05 (s, 1H),8.37 (s, 1H), 8.19 (s, 1H), 8.17 (dd, J=8.8, 2.0 Hz, 1H), 7.92 (d, J=8.7Hz, 1H), 7.83-7.78 (m, 2H), 7.53 (t, J=7.6 Hz, 2H), 7.43 (t, J=7.4 Hz,1H), 3.96 (q, J=7.0 Hz, 2H), 3.57 (s, 3H), 1.41 (t, J=7.0 Hz, 3H).

Example 431-(6-Phenyl-4-(pyrrolidin-1-yl)quinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 1steps B through F using 4-phenylaniline in step B and pyrrolidine instep E. MS (ESI): mass calcd. for C₂₂H₁₉N₅O₂, 385.1; m/z found, 386.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): 9.09 (s, 1H), 8.51 (s, 1H), 8.24 (s,1H), 8.20 (dd, J=8.7, 1.6 Hz, 1H), 7.96 (d, J=8.7 Hz, 1H), 7.85-7.79 (m,2H), 7.53 (t, J=7.6 Hz, 2H), 7.44 (t, J=7.4 Hz, 1H), 4.16 (s, 4H), 2.05(s, 4H).

Example 441-(6-Phenyl-4-(phenylamino)quinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 1steps B through F using 4-phenylaniline in step B and aniline in step E.MS (ESI): mass calcd. for C₂₄H₁₇N₅O₂, 407.1; m/z found, 408.0 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d₆): 12.81 (s, 1H), 10.39 (s, 1H), 8.94 (s, 1H), 8.86(s, 1H), 8.25 (dd, J=8.7, 1.9 Hz, 1H), 8.14 (d, J=0.6 Hz, 1H), 7.93-7.81(m, 5H), 7.58 (t, J=7.7 Hz, 2H), 7.49 (dd, J=15.4, 7.2 Hz, 3H), 7.25 (t,J=7.4 Hz, 1H).

Example 451-(6-Phenyl-4-(piperidin-1-yl)quinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 1steps B through F using 4-phenylaniline in step B and piperidine in stepE. MS (ESI): mass calcd. for C₂₃H₂₁N₅O₂, 399.1; m/z found, 400.1 [M+H]⁺.¹H NMR (400 MHz, DMSO-d₆): 12.80 (5, 1H), 9.03 (s, 1H), 8.19-8.12 (m,3H), 7.92-7.87 (m, 1H), 7.83-7.77 (m, 2H), 7.54 (t, J=7.6 Hz, 2H), 7.43(t, J=7.4 Hz, 1H), 3.94 (5, 4H), 1.77 (5, 6H).

Example 461-(4-(Diethylamino)-6-phenylquinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 1steps B through F using 4-phenylaniline in step B and diethylamine instep E. MS (ESI): mass calcd. for C₂₂H₂₁N₅O₂, 387.1; m/z found, 388.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): 8.97 (s, 1H), 8.22 (d, J=1.8 Hz, 1H),8.14 (dd, J=8.9, 2.1 Hz, 1H), 8.13 (s, 1H), 7.87 (d, J=8.7 Hz, 1H),7.81-7.75 (m, 2H), 7.54 (t, J=7.7 Hz, 2H), 7.43 (t, J=7.4 Hz, 1H), 3.89(q, J=6.9 Hz, 4H), 1.45 (t, J=7.0 Hz, 6H).

Example 471-(4-((2-Chlorophenyl)amino)-6-phenylquinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 1steps B through F using 4-phenylaniline in step B and 2-chloroaniline instep E. MS (ESI): mass calcd. for C₂₄H₁₆ClN₅O₂, 441.1; m/z found, 442.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): 10.56 (s, 1H), 8.94 (s, 1H), 8.54 (s,1H), 8.29 (dd, J=8.7, 1.9 Hz, 1H), 8.07 (s, 1H), 7.93 (d, J=8.7 Hz, 3H),7.75-7.68 (m, 2H), 7.58 (t, J=7.7 Hz, 2H), 7.62-7.53 (m, 1H), 7.49-7.42(m, 2H).

Example 481-(4-(Azepan-1-yl)-6-phenylquinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 1steps B through F using 4-phenylaniline in step B and homopiperidine instep E. MS (ESI): mass calcd. for C₂₄H₂₃N₅O₂, 413.1; m/z found, 414.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): 12.81 (s, 1H), 9.00 (s, 1H), 8.34 (s,1H), 8.14 (dd, J=8.3, 1.2 Hz, 2H), 7.88 (d, J=8.7 Hz, 1H), 7.81-7.75 (m,2H), 7.53 (t, J=7.7 Hz, 2H), 7.45-7.40 (m, 1H), 4.15-4.02 (m, 4H), 2.01(s, 4H), 1.62 (s, 4H).

Example 491-(4-((Cyclohexylmethyl)amino)-6-phenylquinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 1steps B through F using 4-phenylaniline in step B andN-methylcyclohexylamine in step E. MS (ESI): mass calcd. for C₂₅H₂₅N₅O₂,427.2; m/z found, 428.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): 12.80 (s,1H), 9.02 (s, 1H), 8.97 (s, 1H), 8.70 (s, 1H), 8.19-8.12 (m, 2H),7.89-7.84 (m, 2H), 7.82 (d, J=8.7 Hz, 1H), 7.55 (t, J=7.7 Hz, 2H), 7.44(t, J=7.3 Hz, 1H), 3.56 (s, 3H), 1.92-1.83 (m, 3H), 1.81-1.72 (m, 2H),1.64 (s, 1H), 1.31-1.13 (m, 3H), 1.13-1.08 (m, 2H).

Example 501-(4-Cyanamido-6-phenylquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid

The titled compound was prepared in a manner analogous to EXAMPLE 1steps B through F using 4-phenylaniline in step B and sodium cyanamidein step E. MS (ESI): mass calcd. for C₁₉H₁₂N₆O₂, 356.1; m/z found, 357.1[M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆): 13.15 (s, 1H), 8.91 (s, 1H), 8.40 (s,1H), 8.35 (s, 1H), 8.19 (dd, J=8.7, 2.0 Hz, 1H), 7.97 (d, J=8.6 Hz, 1H),7.76 (d, J=7.4 Hz, 2H), 7.52 (t, J=7.6 Hz, 2H), 7.43 (t, J=7.4 Hz, 1H).

Example 511-(4-(Cyclopropylamino)-6-phenylquinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 1steps B through F using 4-phenylaniline in step B and cyclopropylaminein step E. MS (ESI): mass calcd. for C₂₁H₁₇N₅O₂, 371.1; m/z found, 372.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): 9.36 (5, 1H), 9.14 (5, 1H), 8.75 (5,1H), 8.24-8.22 (m, 1H), 8.21 (dd, J=8.7, 1.9 Hz, 1H), 7.90 (d, J=8.7 Hz,1H), 7.88-7.85 (m, 2H), 7.55 (dd, J=10.5, 4.8 Hz, 2H), 7.48-7.40 (m,1H), 3.44-3.38 (m, 1H), 1.00-0.90 (m, 2H), 0.89-0.80 (m, 2H).

Example 521-(4-(tert-Butylamino)-6-phenylquinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 1steps B through F using 4-phenylaniline in step B and tert-butylamine instep E. MS (ESI): mass calcd. for C₂₂H₂₁N₅O₂, 387.1; m/z found, 388.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): 8.93 (s, 1H), 8.77 (s, 1H), 8.23 (s,1H), 8.21 (s, 1H), 8.16 (dd, J=8.7, 1.9 Hz, 1H), 7.87 (dd, J=12.5, 5.0Hz, 3H), 7.55 (t, J=7.6 Hz, 2H), 7.44 (t, J=8.4 Hz, 1H), 1.66 (s, 9H).

Example 53 1-(4-Amino-6-phenylquinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 1steps B through F using 4-phenylaniline in step B and ammonia in dioxanein step E. MS (ESI): mass calcd. for C₁₈H₁₃N₅O₂, 331.1; m/z found, 332.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): 13.34-12.10 (m, 1H), 8.98 (s, 1H),8.73 (s, 1H), 8.68 (d, J=1.9 Hz, 1H), 8.55 (s, 1H), 8.21 (dd, J=8.7, 1.9Hz, 1H), 8.15 (s, 1H), 7.89-7.83 (m, 3H), 7.55 (t, J=7.7 Hz, 2H), 7.43(t, J=7.4 Hz, 1H).

Example 541-(6-Phenyl-4-thiomorpholinoquinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 1steps B through F using 4-phenylaniline in step B and thiomorpholine instep E. MS (ESI): mass calcd. for C₂₂H₁₉N₅O₂S, 417.1; m/z found, 418.1[M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆): 12.79 (s, 1H), 9.04 (s, 1H), 8.18(dd, J=8.7, 2.0 Hz, 1H), 8.15 (d, J=1.9 Hz, 1H), 8.14 (d, J=0.7 Hz, 1H),7.92 (d, J=8.7 Hz, 1H), 7.85-7.80 (m, 2H), 7.57-7.52 (m, 2H), 7.46-7.41(m, 1H), 4.26-4.16 (m, 4H), 2.94-2.79 (m, 4H).

Example 551-(4-(4-Acetamidopiperidin-1-yl)-6-phenylquinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 1steps B through F using 4-phenylaniline in step B andN-(piperidin-4-yl)acetamide in step E. MS (ESI): mass calcd. forC₂₅H₂₄N₆O₃, 456.1; m/z found, 457.1 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆):12.81 (s, 1H), 9.05 (s, 1H), 8.17 (d, J=8.7 Hz, 1H), 8.14 (s, 2H), 7.92(d, J=8.7 Hz, 2H), 7.80 (dd, J=8.3, 1.1 Hz, 2H), 7.54 (dd, J=10.5, 4.9Hz, 2H), 7.44-7.38 (m, 1H), 4.48-4.36 (m, 2H), 4.05-3.91 (m, 1H), 3.52(t, J=11.5 Hz, 2H), 2.00 (d, J=9.5 Hz, 2H), 1.84 (s, 3H), 1.62-1.51 (m,2H).

Example 561-(6-Phenyl-4-((tetrahydro-2H-pyran-4-yl)amino)quinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 1steps B through F using 4-phenylaniline in step B and4-aminotetrahydropyran in step E. MS (ESI): mass calcd. for C₂₃H₂₁N₅O₃,415.1; m/z found, 416.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): 9.12 (s, 1H),9.05 (s, 1H), 8.79 (s, 1H), 8.22 (s, 1H), 8.20 (dd, J=8.8, 1.9 Hz, 1H),7.89 (dd, J=8.2, 6.7 Hz, 3H), 7.56 (t, J=7.6 Hz, 2H), 7.45 (t, J=7.4 Hz,1H), 4.76-4.60 (m, 1H), 3.98 (dd, J=11.2, 3.2 Hz, 2H), 3.56 (dd, J=11.8,10.1 Hz, 2H), 1.99 (dd, J=12.5, 2.4 Hz, 2H), 1.80-1.72 (m, 2H).

Example 571-(4-(4-Methyl-1,4-diazepan-1-yl)-6-phenylquinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 1steps B through F using 4-phenylaniline in step B andN-methylhomopiperazine in step E. MS (ESI): mass calcd. for C₂₄H₂₄N₆O₂,428.2; m/z found, 429.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): 12.10-11.18(m, 1H), 9.05 (s, 1H), 8.32 (s, 1H), 8.16 (dd, J=8.7, 1.8 Hz, 1H), 8.14(s, 1H), 7.89 (d, J=8.7 Hz, 1H), 7.83-7.79 (m, 2H), 7.53 (t, J=7.6 Hz,2H), 7.43 (t, J=7.3 Hz, 1H), 4.28 (d, J=16.6 Hz, 2H), 4.24 (s, 2H), 3.51(s, 2H), 3.18 (s, 2H), 2.69 (s, 3H), 2.35 (s, 2H).

Example 581-(4-Morpholino-6-phenylquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid

The titled compound was prepared in a manner analogous to EXAMPLE 1steps B through F using 4-phenylaniline in step B and morpholine in stepE. MS (ESI): mass calcd. for C₂₂H₁₉N₅O₃, 401.1; m/z found, 402.1 [M+H]⁺.¹H NMR (500 MHz, DMSO-d₆): 13.09-12.49 (m, 1H), 9.09 (s, 1H), 8.21 (s,1H), 8.18 (dd, J=8.7, 2.0 Hz, 1H), 8.16 (s, 1H), 7.94 (d, J=8.7 Hz, 1H),7.82 (dd, J=8.3, 1.1 Hz, 2H), 7.54 (dd, J=10.5, 4.9 Hz, 2H), 7.46-7.41(m, 1H), 4.12-4.01 (m, 4H), 3.88-3.77 (m, 4H).

Example 591-(4-(4-Cyanopiperidin-1-yl)-6-phenylquinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 1steps B through F using 4-phenylaniline in step B and 4-cyanopiperidinein step E. MS (ESI): mass calcd. for C₂₄H₂₀N₆O₂, 424.1; m/z found, 425.1[M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆): 13.35-12.09 (m, 1H), 9.09 (s, 1H),8.19 (dd, J=8.7, 1.9 Hz, 1H), 8.17 (d, J=4.6 Hz, 2H), 7.94 (d, J=8.6 Hz,1H), 7.86-7.80 (m, 2H), 7.55 (dd, J=10.5, 4.9 Hz, 2H), 7.47-7.41 (m,1H), 4.29-4.16 (m, 2H), 3.87-3.76 (m, 2H), 3.30-3.24 (m, 1H), 2.21-2.11(m, 2H), 2.08-1.97 (m, 2H).

Example 601-(6-(4-Chlorophenoxy)-4-(diethylamino)quinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 1steps B through F using 4-(4-chloro)phenoxyaniline in step B anddiethylamine in step E. MS (ESI): mass calcd. for C₂₂H₂₀ClN₅O₃, 437.1;m/z found, 438.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): 12.77 (s, 1H), 8.93(s, 1H), 8.11 (s, 1H), 7.84 (d, J=9.1 Hz, 1H), 7.66 (dd, J=9.1, 2.6 Hz,1H), 7.56-7.50 (m, 2H), 7.31 (d, J=2.6 Hz, 1H), 7.27-7.17 (m, 2H), 3.68(q, J=6.9 Hz, 4H), 1.20 (t, J=7.0 Hz, 6H).

Example 611-(6-(4-Chlorophenoxy)-4-(pyrrolidin-1-yl)quinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 1steps B through F using 4-(4-chloro)phenoxyaniline in step B andpyrrolidine in step E. MS (ESI): mass calcd. for C₂₂H₁₈ClN₅O₃, 435.1;m/z found, 436.1 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆): 12.74 (s, 1H), 8.98(s, 1H), 8.09 (s, 1H), 7.87 (d, J=2.1 Hz, 1H), 7.80 (d, J=9.0 Hz, 1H),7.57 (dd, J=9.0, 2.5 Hz, 1H), 7.49-7.44 (m, 2H), 7.15-7.08 (m, 2H), 3.89(s, 4H), 1.97 (t, J=6.3 Hz, 4H).

Example 621-(6-(4-Chlorophenoxy)-4-(cyclopropylamino)quinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 1steps B through F using 4-(4-chloro)phenoxyaniline in step B andcyclopropylamine in step E. MS (ESI): mass calcd. for C₂₁H₁₆ClN₅O₃,421.0; m/z found, 422.0 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆): 12.78 (s,1H), 9.06 (s, 1H), 8.66 (d, J=3.6 Hz, 1H), 8.12 (s, 1H), 8.04 (d, J=2.1Hz, 1H), 7.82 (d, J=9.0 Hz, 1H), 7.58 (dd, J=9.0, 2.5 Hz, 1H), 7.50-7.43(m, 2H), 7.14-7.06 (m, 2H), 3.26-3.15 (m, 1H), 0.91-0.83 (m, 2H),0.73-0.67 (m, 2H).

Example 631-(6-(4-Chlorophenoxy)-4-(piperidin-1-yl)quinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 1steps B through F using 4-(4-chloro)phenoxyaniline in step B andpiperidine in step E. MS (ESI): mass calcd. for C₂₃H₂₀ClN₅O₃, 449.1; m/zfound, 450.1 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆): 12.78 (s, 1H), 8.99 (s,1H), 8.11 (s, 1H), 7.88 (d, J=9.1 Hz, 1H), 7.64 (dd, J=9.1, 2.6 Hz, 1H),7.54-7.48 (m, 2H), 7.34 (d, J=2.5 Hz, 1H), 7.24-7.18 (m, 2H), 3.75 (d,J=5.3 Hz, 4H), 1.68 (s, 2H), 1.63 (d, J=3.7 Hz, 4H).

Example 641-(6-(4-Chlorophenoxy)-4-((cyclohexylmethyl)amino)quinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 1steps B through F using 4-(4-chloro)phenoxyaniline in step B andcyclohexylmethanamine in step E. MS (ESI): mass calcd. for C₂₅H₂₄ClN₅O₃,477.2; m/z found, 478.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): 12.78 (s,1H), 8.98 (s, 1H), 8.67 (s, 1H), 8.12 (s, 1H), 8.10 (d, J=2.6 Hz, 1H),7.80 (d, J=9.0 Hz, 1H), 7.57 (dd, J=9.0, 2.6 Hz, 1H), 7.49-7.44 (m, 2H),7.14-7.09 (m, 2H), 3.48 (t, J=5.9 Hz, 2H), 1.77 (d, J=11.7 Hz, 3H), 1.67(t, J=16.5 Hz, 3H), 1.19 (t, J=11.0 Hz, 3H), 1.03 (t, J=11.3 Hz, 2H).

Example 651-(6-(4-Chlorophenoxy)-4-(4-cyanopiperidin-1-yl)quinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 1steps B through F using 4-(4-chloro)phenoxyaniline in step B and4-cyanopiperidine in step E. MS (ESI): mass calcd. for C₂₄H₁₉ClN₆O₃,474.1; m/z found, 475.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): 12.80 (s,1H), 9.03 (s, 1H), 8.12 (s, 1H), 7.91 (d, J=9.1 Hz, 1H), 7.65 (dd,J=9.1, 2.6 Hz, 1H), 7.53-7.49 (m, 2H), 7.42 (d, J=2.6 Hz, 1H), 7.22-7.17(m, 2H), 4.08-3.92 (m, 2H), 3.70-3.55 (m, 2H), 3.27-3.18 (m, 1H), 2.03(d, J=5.9 Hz, 2H), 1.88-1.72 (m, 2H).

Example 661-(4-(Azepan-1-yl)-6-(4-chlorophenoxy)quinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 1steps B through F using 4-(4-chloro)phenoxyaniline in step B andhomopiperidine in step E. MS (ESI): mass calcd. for C₂₄H₂₂ClN₅O₃, 474.1;m/z found, 475.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): 12.80 (s, 1H), 9.03(s, 1H), 8.12 (s, 1H), 7.91 (d, J=9.1 Hz, 1H), 7.65 (dd, J=9.1, 2.6 Hz,1H), 7.53-7.49 (m, 2H), 7.42 (s, 1H), 7.22-7.17 (m, 2H), 4.08-3.92 (m,2H), 3.70-3.55 (m, 2H), 3.27-3.18 (m, 1H), 2.03 (d, J=5.9 Hz, 2H),1.88-1.72 (m, 2H).

Example 671-(6-(4-Chlorophenoxy)-4-thiomorpholinoquinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 1steps B through F using 4-(4-chloro)phenoxyaniline in step B andthiomorpholine in step E. MS (ESI): mass calcd. for C₂₂H₁₈ClN₅O₃S,467.1; m/z found, 468.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): 8.81 (s, 1H),7.94 (s, 1H), 7.89 (d, J=9.1 Hz, 1H), 7.64 (dd, J=9.1, 2.7 Hz, 1H),7.55-7.47 (m, 2H), 7.34 (d, J=2.7 Hz, 1H), 7.24-7.17 (m, 2H), 4.04-3.95(m, 4H), 2.82-2.73 (m, 4H).

Example 681-(6-(4-Chlorophenoxy)-4-((tetrahydro-2H-pyran-4-yl)amino)quinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 1steps B through F using 4-(4-chloro)phenoxyaniline in step B and4-aminotetrahydropyran in step E. MS (ESI): mass calcd. forC₂₃H₂₀ClN₅O₄, 465.1; m/z found, 466.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆):12.81 (s, 1H), 9.02 (s, 1H), 8.41 (d, J=7.3 Hz, 1H), 8.21 (s, 1H), 8.13(s, 1H), 7.81 (d, J=9.1 Hz, 1H), 7.59 (dd, J=8.9, 2.3 Hz, 1H), 7.50-7.43(m, 2H), 7.15-7.04 (m, 2H), 4.62-4.43 (m, 1H), 3.94 (d, J=8.6 Hz, 2H),3.49-3.44 (m, 2H), 1.95-1.82 (m, 2H), 1.68-1.52 (m, 2H).

Example 691-(6-(4-Chlorophenoxy)-4-(phenylamino)quinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 1steps B through F using 4-(4-chloro)phenoxyaniline in step B and anilinein step E. MS (ESI): mass calcd. for C₂₄H₁₆ClN₅O₃, 457.1; m/z found,458.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): 12.78 (s, 1H), 10.16 (s, 1H),8.83 (s, 1H), 8.39 (d, J=2.5 Hz, 1H), 8.13 (s, 1H), 7.92-7.85 (m, 3H),7.67 (dd, J=9.0, 2.6 Hz, 1H), 7.53-7.43 (m, 4H), 7.22 (t, J=7.4 Hz, 1H),7.19-7.12 (m, 2H).

Example 701-(4-(4-Acetamidopiperidin-1-yl)-6-(4-chlorophenoxy)quinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 1steps B through F using 4-(4-chloro)phenoxyaniline in step B andN-(piperidin-4-yl)acetamide in step E. MS (ESI): mass calcd. forC₂₅H₂₃ClN₆O₄, 506.2; m/z found, 507.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆):12.83 (s, 1H), 9.01 (s, 1H), 8.13 (s, 1H), 7.89 (dd, J=8.4, 4.7 Hz, 2H),7.65 (dd, J=9.1, 2.6 Hz, 1H), 7.55-7.45 (m, 2H), 7.38 (d, J=2.5 Hz, 1H),7.26-7.15 (m, 2H), 4.26 (d, J=13.4 Hz, 2H), 3.99-3.78 (m, 1H), 3.36 (d,J=11.4 Hz, 2H), 1.88 (d, J=9.9 Hz, 2H), 1.80 (s, 3H), 1.48 (dd, J=20.8,10.3 Hz, 2H).

Example 711-(6-(4-Chlorophenoxy)-4-(4-methyl-1,4-diazepan-1-yl)quinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 1steps B through F using 4-(4-chloro)phenoxyaniline in step B andN-methylhomopiperazine in step E. MS (ESI): mass calcd. forC₂₄H₂₃ClN₆O₃, 484.2; m/z found, 479.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆):13.04-11.93 (m, 1H), 9.03 (s, 1H), 8.13 (s, 1H), 7.88 (d, J=9.1 Hz, 1H),7.68 (d, J=2.4 Hz, 1H), 7.63 (dd, J=9.1, 2.6 Hz, 1H), 7.54-7.43 (m, 2H),7.18-7.10 (m, 2H), 4.05 (s, 3H), 3.47-3.32 (m, 3H), 3.29-3.14 (m, 2H),2.74 (s, 3H), 2.28 (s, 2H).

Example 721-(4-(tert-Butylamino)-6-phenoxyquinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 1steps B through F using 4-phenoxyaniline in step B and tert-butylaminein step E. MS (ESI): mass calcd. for C₂₂H₂₁N₅O₃, 403.2; m/z found, 404.2[M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆): 12.80 (s, 1H), 8.91 (s, 1H), 8.37 (d,J=2.6 Hz, 1H), 8.13 (s, 1H), 7.77 (d, J=9.1 Hz, 2H), 7.51 (dd, J=9.0,2.6 Hz, 1H), 7.43-7.37 (m, 2H), 7.17-7.11 (m, 1H), 7.06-6.97 (m, 2H),1.60 (s, 9H).

Example 731-(6-Phenoxy-4-(pyrrolidin-1-yl)quinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 1steps B through F using 4-phenoxyaniline in step B and pyrrolidine instep E. MS (ESI): mass calcd. for C₂₂H₁₉N₅O₃, 401.2; m/z found, 402.2[M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆): 12.74 (s, 1H), 8.99 (s, 1H), 8.09 (s,1H), 7.83 (d, J=2.6 Hz, 1H), 7.81 (d, J=9.0 Hz, 1H), 7.56 (dd, J=9.0,2.6 Hz, 1H), 7.47-7.40 (m, 2H), 7.22-7.16 (m, 1H), 7.13-7.08 (m, 2H),3.88 (s, 4H), 1.96 (t, J=6.4 Hz, 4H).

Example 741-(4-(Diethylamino)-6-phenoxyquinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 1steps B through F using 4-phenoxyaniline in step B and diethylamine instep E. MS (ESI): mass calcd. for C₂₂H₂₁N₅O₃, 403.2; m/z found, 404.2[M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆): 12.75 (s, 1H), 8.92 (s, 1H), 8.10 (s,1H), 7.84 (d, J=9.1 Hz, 1H), 7.65 (dd, J=9.1, 2.4 Hz, 1H), 7.50 (t,J=7.9 Hz, 2H), 7.27 (dd, J=8.9, 5.0 Hz, 2H), 7.21 (d, J=7.8 Hz, 2H),3.65 (q, J=6.9 Hz, 4H), 1.15 (t, J=6.9 Hz, 6H).

Example 751-(4-(Cyclopropylamino)-6-phenoxyquinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 1steps B through F using 4-phenoxyaniline in step B and cyclopropylaminein step E. MS (ESI): mass calcd. for C₂₁H₁₇N₅O₃, 387.1; m/z found, 388.2[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): 12.83 (5, 1H), 9.08 (5, 1H), 8.80 (d,J=3.4 Hz, 1H), 8.15 (5, 1H), 8.11 (d, J=2.6 Hz, 1H), 7.83 (d, J=9.0 Hz,1H), 7.55 (dd, J=9.0, 2.6 Hz, 1H), 7.45-7.38 (m, 2H), 7.20-7.13 (m, 1H),7.09-7.03 (m, 2H), 3.27-3.14 (m, 1H), 0.96-0.83 (m, 2H), 0.77-0.69 (m,2H).

Example 761-(6-Phenoxy-4-((tetrahydro-2H-pyran-4-yl)amino)quinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 1steps B through F using 4-phenoxyaniline in step B and4-aminotetrahydropyran in step E. MS (ESI): mass calcd. for C₂₃H₂₁N₅O₄,431.2; m/z found, 432.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): 12.78 (s,1H), 9.01 (s, 1H), 8.41 (d, J=7.4 Hz, 1H), 8.22 (d, J=2.5 Hz, 1H), 8.12(s, 1H), 7.80 (d, J=9.0 Hz, 1H), 7.54 (dd, J=9.0, 2.6 Hz, 1H), 7.45-7.37(m, 2H), 7.16 (t, J=7.4 Hz, 1H), 7.05 (dd, J=8.7, 1.0 Hz, 2H), 4.53 (dd,J=11.4, 4.1 Hz, 1H), 3.94 (d, J=8.8 Hz, 2H), 3.53-3.47 (m, 2H),2.00-1.90 (m, 2H), 1.72-1.63 (m, 2H).

Example 771-(4-(Dimethylamino)-7-phenoxyquinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

Step A: Preparation of Ethyl1-(N-(ethoxycarbonyl)-N′-(3-phenoxyphenyl)carbamimidoyl)-1H-pyrazole-4-carboxylate.To a mixture of 3-phenoxyaniline (0.93 g, 5.0 mmol) and DCM (17 mL) neatethyl isocyanatoformate (0.65 mL, 5.5 mmol) was added and the resultingsolution was stirred for 15 min. Ethyl pyrazole-4-carboxylate (0.77 g,5.5 mmol), and neat diisopropylcarbodiimide (0.78 mL, 5.0 mmol) wereadded sequentially to the reaction mixture. The solution was stirred atrt for 24 h, and then concentrated. The residue was stirred with ether(10 mL) for 3 h in an ice bath, and then filtered. The residue waspurified by FCC (0 to 25% EtOAc/hexanes) to yield the title compound(1.6 g, 76%, ca 70% purity). MS (ESI/CI): mass calcd. for C₂₂H₂₂N₄O₅,422.1; m/z found, 423.3 [M+H]⁺.

Step B: Preparation of ethyl1-(4-oxo-7-phenoxy-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate.To a solution of ethyl1-(N-(ethoxycarbonyl)-N′-(3-phenoxyphenyl)carbamimidoyl)-1H-pyrazole-4-carboxylate(1.51 g, ca 2.51 mmol) in dichloroethane (DCE) (18 mL), neat TiCl₄ (1.18mL, 10.7 mmol) was added over 2 min. The mixture was then heated toreflux for 2 h, and then cooled in an ice bath. EtOH (50 mL) was added,and the mixture was stirred for 3 h. The resulting precipitate wascollected by filtration, washed with cold EtOH, and dried to provide thetitled compound (0.77 g, 57%). MS (ESI/CI): mass calcd. for C₂₀H₁₆N₄O₄,376.1; m/z found, 377.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): 12.85 (s,1H), 9.00 (d, J=0.5 Hz, 1H), 8.31 (s, 1H), 8.13 (d, J=8.8 Hz, 1H),7.58-7.45 (m, 2H), 7.38-7.27 (m, 1H), 7.26-7.20 (m, 2H), 7.18 (dd,J=8.8, 2.4 Hz, 1H), 6.98 (s, 1H), 4.39-4.13 (m, 2H), 1.42-1.21 (m, 3H).

Step C: Preparation of ethyl1-(4-chloro-7-phenoxyquinazolin-2-yl)-1H-pyrazole-4-carboxylate. Amixture of the above ethyl1-(4-oxo-7-phenoxy-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate(0.31 g, 0.82 mmol), and POCl₃ (3.08 mL, 32.9 mmol), was heated toreflux for 3 h. The mixture was allowed to cool to rt and thenconcentrated. The residue was taken up in a minimal amount of DCM andpurified by FCC (0 to 25% EtOAc/hexanes) to yield the title compound(250 mg, 77%). ¹H NMR (600 MHz, DMSO-d₆): 9.06 (d, J=0.7 Hz, 1H), 8.35(d, J=9.2 Hz, 1H), 8.23 (dd, J=10.6, 6.6 Hz, 1H), 7.63-7.59 (m, 1H),7.60-7.54 (m, 2H), 7.41-7.36 (m, 1H), 7.31-7.29 (m, 2H), 7.18 (d, J=2.4Hz, 1H), 4.30 (q, J=7.1 Hz, 2H), 1.35-1.24 (t, J=7.2 Hz, 3H).

Step D: Preparation of ethyl1-(4-(dimethylamino)-7-phenoxyquinazolin-2-yl)-1H-pyrazole-4-carboxylate.A THF solution of dimethylamine (2M, 0.44 mL, 0.88 mmol) was added to asolution of the above ethyl1-(4-chloro-7-phenoxyquinazolin-2-yl)-1H-pyrazole-4-carboxylate (70 mg,0.18 mmol) and THF (1.4 mL). The mixture was stirred 1 h, and thenconcentrated. The residue was triturated with ethanol, providing thetitled compound (45 mg, 63%). MS (ESI/CI): mass calcd. for C₂₂H₂₁N₅O₃,403.1; m/z found, 404.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): 9.02 (s, 1H),8.31 (d, J=9.3 Hz, 1H), 8.12 (s, 1H), 7.53 (dd, J=11.1, 4.8 Hz, 2H),7.32 (t, J=7.4 Hz, 1H), 7.27-7.21 (m, 2H), 7.18 (dd, J=9.3, 2.7 Hz, 1H),6.96 (d, J=2.7 Hz, 1H), 4.27 (q, J=7.1 Hz, 2H), 3.46 (s, 6H), 1.30 (t,J=7.1 Hz, 3H).

Step E: Preparation of1-(4-(dimethylamino)-7-phenoxyquinazolin-2-yl)-1H-pyrazole-4-carboxylicacid. A mixture of ethyl1-(4-(dimethylamino)-7-phenoxyquinazolin-2-yl)-1H-pyrazole-4-carboxylate(35 mg, 0.09 mmol), 1M aqueous KOH (0.43 mL, 0.43 mmol), and THF (1.3mL) was heated to 40° C. for 48 h with rapid stirring. The mixture wasthen concentrated, cooled in an ice bath, and 1M aqueous HCl was addeduntil the mixture was slightly acidic (pH ca 5-6). The resultingprecipitate was collected by filtration, washed with water, and dried tofurnish the titled compound (22 mg, 68%). MS (ESI): mass calcd. forC₂₀H₁₇N₅O₃, 375.1; m/z found, 376.3 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆):12.73 (s, 1H), 8.98 (d, J=0.6 Hz, 1H), 8.31 (d, J=9.3 Hz, 1H), 8.07 (s,1H), 7.52 (ddd, J=7.6, 5.9, 2.2 Hz, 2H), 7.36-7.28 (m, 1H), 7.28-7.20(m, 2H), 7.17 (dd, J=9.3, 2.7 Hz, 1H), 6.97 (d, J=2.7 Hz, 1H), 3.46 (s,6H).

Example 781-(7-Phenoxy-4-(pyrrolidin-1-yl)quinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 77using 3-phenoxyaniline in step A and pyrrolidine in step D. MS (ESI):mass calcd. for C₂₂H₁₉N₅O₃, 401.1; m/z found, 402.3 [M+H]⁺. ¹H NMR (500MHz, DMSO-d₆): 12.72 (s, 1H), 8.97 (d, J=0.6 Hz, 1H), 8.38 (d, J=9.3 Hz,1H), 8.06 (d, J=0.6 Hz, 1H), 7.56-7.46 (m, 2H), 7.35-7.27 (m, 1H),7.26-7.19 (m, 2H), 7.16 (dd, J=9.3, 2.7 Hz, 1H), 6.97 (d, J=2.7 Hz, 1H),3.97 (s, 4H), 2.01 (s, 4H).

Example 791-(7-Phenoxy-4-(piperidin-1-yl)quinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 77using 3-phenoxyaniline in step A and piperidine in step D. MS (ESI):mass calcd. for C₂₃H₂₁N₅O₃, 415.1; m/z found, 416.3 [M+H]⁺. ¹H NMR (500MHz, DMSO-d₆): 12.74 (s, 1H), 8.97 (d, J=0.7 Hz, 1H), 8.08 (d, J=0.7 Hz,1H), 8.04 (d, J=9.2 Hz, 1H), 7.56-7.49 (m, 2H), 7.32 (t, J=7.4 Hz, 1H),7.25-7.21 (m, 3H), 6.99 (d, J=2.6 Hz, 1H), 3.86 (s, 4H), 1.74 (s, 6H).

Example 801-(4-(Dimethylamino)-7-phenylquinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 77using 3-phenylaniline in step A and dimethylamine in step D. MS (ESI):mass calcd. for C₂₀H₁₇N₅O₂, 359.1; m/z found, 360.3 [M+H]⁺. ¹H NMR (400MHz, DMSO-d₆): 9.13 (d, J=0.5 Hz, 1H), 8.40 (d, J=8.8 Hz, 1H), 8.24 (s,1H), 8.15 (d, J=1.9 Hz, 1H), 7.89-7.81 (m, 3H), 7.59-7.48 (m, 2H),7.53-7.44 (m, 1H), 3.59 (s, 6H).

Example 811-(7-Phenyl-4-(pyrrolidin-1-yl)quinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 77using 3-phenylaniline in step A and pyrrolidine in step D. MS (ESI):mass calcd. for C₂₂H₁₉N₅O₂, 385.1; m/z found, 386.3 [M+H]⁺. ¹H NMR (400MHz, DMSO-d₆): 9.08 (d, J=0.5 Hz, 1H), 8.45 (d, J=8.9 Hz, 1H), 8.21 (s,1H), 8.12 (d, J=1.8 Hz, 1H), 7.90-7.78 (m, 3H), 7.62-7.53 (m, 2H),7.53-7.45 (m, 1H), 4.07 (s, 4H), 2.05 (s, 4H).

Example 821-(7-Phenyl-4-(piperidin-1-yl)quinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 77using 3-phenylaniline in step A and piperidine in step D. MS (ESI): masscalcd. for C₂₃H₂₁N₅O₂, 399.1; m/z found, 400.3 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d₆): 12.80 (s, 1H), 9.03 (d, J=0.5 Hz, 1H), 8.13 (d, J=0.5 Hz, 1H),8.10 (d, J=8.7 Hz, 1H), 8.06 (d, J=1.9 Hz, 1H), 7.89-7.80 (m, 3H),7.60-7.52 (m, 2H), 7.51-7.45 (m, 1H), 3.92 (s, 4H), 1.77 (s, 6H).

Example 831-(4-(Diethylamino)-7-phenoxyquinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 77using 3-phenoxyaniline in step A and diethylamine in step D. MS (ESI):mass calcd. for C₂₂H₂₁N₅O₃, 403.1; m/z found, 404.3 [M+H]⁺. ¹H NMR (600MHz, DMSO-d₆): 8.91 (d, J=0.7 Hz, 1H), 8.09-8.07 (m, 2H), 7.56-7.48 (m,2H), 7.35-7.28 (m, 1H), 7.25-7.22 (m, 2H), 7.20 (dd, J=9.3, 2.7 Hz, 1H),6.99 (d, J=2.7 Hz, 1H), 3.82 (q, J=7.0 Hz, 4H), 1.38 (t, J=7.0 Hz, 6H).

Example 841-(4-((Cyclohexylmethyl)amino)-7-phenoxyquinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 77using 3-phenoxyaniline in step A and cyclohexylmethanamine in step D. MS(ESI): mass calcd. for C₂₅H₂₅N₅O₃, 443.2; m/z found, 444.4 [M+H]⁺. ¹HNMR (600 MHz, DMSO-d₆): 12.74 (s, 1H), 8.96 (s, 1H), 8.75 (s, 1H), 8.38(d, J=9.1 Hz, 1H), 8.09 (s, 1H), 7.56-7.46 (m, 2H), 7.30 (t, J=7.4 Hz,1H), 7.26 (dd, J=9.0, 2.5 Hz, 1H), 7.21 (dd, J=8.6, 1.0 Hz, 2H), 6.98(d, J=2.4 Hz, 1H), 3.51 (t, J=6.0 Hz, 2H), 1.80-1.62 (m, 7H), 1.27-1.11(m, 2H), 1.04 (m, 2H).

Example 851-(4-(4-Isopropylpiperidin-1-yl)-7-phenoxyquinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 77using 3-phenoxyaniline in step A and 4-isopropylpiperidine in step D. MS(ESI): mass calcd. for C₂₆H₂₇N₅O₃, 457.2; m/z found, 458.4 [M+H]⁺. ¹HNMR (500 MHz, DMSO-d₆): 12.75 (s, 1H), 8.97 (d, J=0.7 Hz, 1H), 8.08 (d,J=0.7 Hz, 1H), 8.06 (d, J=9.2 Hz, 1H), 7.57-7.48 (m, 2H), 7.34-7.31 (m,1H), 7.24-7.23 (m, 3H), 6.99 (d, J=2.6 Hz, 1H), 4.54 (d, J=13.0 Hz, 2H),3.22 (t, J=12.0 Hz, 2H), 1.84 (d, J=9.8 Hz, 2H), 1.56-1.33 (m, 4H), 0.91(d, J=6.6 Hz, 6H)

Example 861-(4-(Cyclopropylamino)-7-phenoxyquinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 77using 3-phenoxyaniline in step A and cyclopropylamine in step D. MS(ESI): mass calcd. for C₂₁H₁₇N₅O₃, 387.1; m/z found, 388.3 [M+H]⁺. ¹HNMR (600 MHz, DMSO-d₆): 12.74 (5, 1H), 9.01 (5, 1H), 8.64 (d, J=3.9 Hz,1H), 8.31 (d, J=9.1 Hz, 1H), 8.06 (s, 1H), 7.55-7.45 (m, 2H), 7.31-7.29(m, 1H), 7.24 (dd, J=9.0, 2.5 Hz, 1H), 7.22-7.19 (m, 2H), 6.95 (d, J=2.5Hz, 1H), 3.25-3.20 (m, 1H), 0.93-0.84 (m, 2H), 0.76-0.69 (m, 2H).

Example 871-(4-(Azepan-1-yl)-7-phenoxyquinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 77using 3-phenoxyaniline in step A and homopiperidine in step D. MS (ESI):mass calcd. for C₂₄H₂₃N₅O₃, 429.1; m/z found, 430.3 [M+H]⁺. ¹H NMR (600MHz, DMSO-d₆): 12.72 (s, 1H), 8.92 (s, 1H), 8.21 (d, J=9.3 Hz, 1H), 8.06(s, 1H), 7.56-7.47 (m, 2H), 7.31 (t, J=7.4 Hz, 1H), 7.23 (dd, J=8.5, 0.9Hz, 2H), 7.16 (dd, J=9.3, 2.7 Hz, 1H), 6.97 (d, J=2.7 Hz, 1H), 4.08-3.94(m, 4H), 1.95 (s, 4H), 1.58 (s, 4H).

Example 881-(4-(Diethylamino)-6-(piperidin-1-yl)quinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 77using 4-piperidin-1-yl-aniline in step A and diethylamine in step D. MS(ESI): mass calcd. for C₂₁H₂₆N₆O₂, 394.2; m/z found, 395.3 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d₆): 8.89 (5, 1H), 8.06 (s, 1H), 7.65 (br s, 2H),7.18 (s, 1H), 3.78 (q, J=7.0 Hz, 4H), 3.28-3.23 (m, 4H), 1.72-1.64 (m,4H), 1.62-1.54 (m, 2H), 1.40 (t, J=7.0 Hz, 6H).

Example 891-(4-Morpholino-7-phenoxyquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid

The titled compound was prepared in a manner analogous to EXAMPLE 77using 3-phenoxy aniline in step A and morpholine in step D. MS (ESI):mass calcd. for C₂₂H₁₉N₅O₄, 417.1; m/z found, 418.1 [M+H]⁺. ¹H NMR (600MHz, DMSO-d₆): 9.02 (5, 1H), 8.13-8.12 (m, 1H), 8.11 (s, 1H), 7.59-7.45(m, 2H), 7.33 (t, J=7.4 Hz, 1H), 7.28-7.18 (m, 3H), 7.04 (d, J=2.5 Hz,1H), 3.94-3.92 (m, 4H), 3.88-3.76 (m, 4H).

Example 901-(7-Phenoxy-4-thiomorpholinoquinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 77using 3-phenoxy aniline in step A and thiomorpholine in step D. MS(ESI): mass calcd. for C₂₂H₁₉N₅O₃S, 433.1; m/z found, 434.1 [M+H]⁺. ¹HNMR (600 MHz, DMSO-d₆): 9.04-8.97 (m, 1H), 8.10 (s, 1H), 8.05 (d, J=9.2Hz, 1H), 7.58-7.48 (m, 2H), 7.36-7.29 (m, 1H), 7.28-7.20 (m, 3H), 7.05(d, J=2.5 Hz, 1H), 4.22-4.08 (m, 4H), 2.96-2.86 (m, 4H).

Example 911-(4-(4-Fluoropiperidin-1-yl)-7-phenoxyquinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 77using 3-phenoxy aniline in step A and 4-fluoropiperidine in step D. MS(ESI): mass calcd. for C₂₃H₂₀FN₅O₃, 433.2; m/z found, 434.1 [M+H]⁺. ¹HNMR (600 MHz, DMSO-d₆): 9.02 (s, 1H), 8.14-8.09 (m, 2H), 7.58-7.48 (m,2H), 7.37-7.30 (m, 1H), 7.27-7.20 (m, 3H), 7.06 (d, J=2.5 Hz, 1H),5.14-4.92 (m, 1H), 4.06-3.65 (m, 4H), 2.23-2.03 (m, 2H), 1.97-1.92 (m,2H).

Example 921-(4-(Dibutylamino)-7-phenoxyquinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 77using 3-phenoxy aniline in step A and dibutylamine in step D. MS (ESI):mass calcd. for C₂₆H₂₉N₅O₃, 459.2; m/z found, 460.2 [M+H]⁺. ¹H NMR (600MHz, DMSO-d₆): 8.91 (s, 1H), 8.10 (s, 1H), 8.04 (d, J=9.3 Hz, 1H),7.57-7.48 (m, 2H), 7.37-7.28 (m, 1H), 7.24-7.22 (m, 3H), 7.04 (d, J=2.3Hz, 1H), 3.80-3.77 (m, 4H), 1.79 (dt, J=15.3, 7.7 Hz, 4H), 1.44-1.38 (m,4H), 0.96 (t, J=7.4 Hz, 6H).

Example 931-(4-(Dipropylamino)-7-phenoxyquinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 77using 3-phenoxy aniline in step A and dipropylamine in step D. MS (ESI):mass calcd. for C₂₄H₂₅N₅O₃, 431.2; m/z found, 432.2 [M+H]⁺. ¹H NMR (600MHz, DMSO-d₆): 8.91 (s, 1H), 8.10 (s, 1H), 8.03 (d, J=9.2 Hz, 1H),7.56-7.47 (m, 2H), 7.32 (t, J=7.4 Hz, 1H), 7.23 (dd, J=8.6, 1.0 Hz, 3H),7.04 (s, 1H), 3.77-3.74 (m, 4H), 1.93-1.70 (m, 4H), 0.98-0.96 (m, 6H).

Example 941-(4-(Ethyl(methyl)amino)-7-phenoxyquinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 77using 3-phenoxy aniline in step A and N-methylethylamine in step D. MS(ESI): mass calcd. for C₂₁H₁₉H₅O₃, 389.2; m/z found, 390.1 [M+H]⁺. ¹HNMR (600 MHz, DMSO-d₆): 8.97 (s, 1H), 8.26 (d, J=9.1 Hz, 1H), 8.11 (s,1H), 7.59-7.43 (m, 2H), 7.37-7.29 (m, 1H), 7.24-7.22 (m, 2H), 7.20-7.18(m, 1H), 7.05 (s, 1H), 3.90-3.87 (m, 2H), 3.47 (s, 3H), 1.35 (t, J=7.1Hz, 3H).

Example 951-(4-((2-Methoxyethyl)(methyl)amino)-7-phenoxyquinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 77using 3-phenoxy aniline in step A and 2-methoxy-N-methyl ethylamine instep D. MS (ESI): mass calcd. for C₂₂H₂₁N₅O₄, 419.2; m/z found, 420.1[M+H]⁺. ¹H NMR (600 MHz, DMSO-d₆): 8.98 (s, 1H), 8.36 (d, J=9.2 Hz, 1H),8.10 (s, 1H), 7.57-7.47 (m, 2H), 7.37-7.29 (m, 1H), 7.27-7.21 (m, 2H),7.18 (dd, J=9.3, 2.5 Hz, 1H), 7.04 (s, 1H), 4.07 (t, J=5.5 Hz, 2H),3.77-3.74 (m, 2H), 3.53 (s, 3H), 3.31 (s, 3H).

Example 961-(7-Bromo-4-(diethylamino)quinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 77using 3-bromoaniline in step A and diethylamine in step D. MS (ESI):mass calcd. for C₁₆H₁₆BrN₅O₂, 389.1; m/z found, 390.0 [M+H]⁺. ¹H NMR(600 MHz, DMSO-d₆): 12.75 (s, 1H), 8.94 (d, J=0.7 Hz, 1H), 8.11 (d,J=0.7 Hz, 1H), 7.97 (s, 1H), 7.96 (d, J=2.0 Hz, 2H), 3.83 (q, J=7.0 Hz,4H), 1.44-1.33 (m, 6H).

Example 971-(4-(Cyclohexylamino)-7-phenoxyquinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 77using 3-phenoxyaniline in step A and cyclohexylamine in step D. MS(ESI): mass calcd. for C₂₄H₂₃N₅O₃, 429.2; m/z found, 430.1 [M+H]⁺. ¹HNMR (600 MHz, DMSO-d₆): 8.97 (s, 1H), 8.49-8.45 (m, 2H), 8.11 (s, 1H),7.51 (t, J=7.9 Hz, 2H), 7.30 (t, J=7.4 Hz, 1H), 7.26 (d, J=9.1 Hz, 1H),7.20 (d, J=7.7 Hz, 2H), 7.01 (s, 1H), 4.30 (s, 1H), 2.05-2.00 (m, 2H),1.82-1.80 (m, 2H), 1.70-1.68 (m, 1H), 1.52-1.36 (m, 4H), 1.29-1.13 (m,1H).

Example 981-(4-((Cyclopropylmethyl)amino)-7-phenoxyquinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 77using 3-phenoxyaniline in step A and cyclopropylmethylamine in step D.MS (ESI): mass calcd. for C₂₂H₁₉N₅O₃, 401.2; m/z found, 402.1 [M+H]⁺. ¹HNMR (600 MHz, DMSO-d₆): 8.99 (s, 1H), 8.92 (s, 1H), 8.38 (d, J=8.5 Hz,1H), 8.10 (s, 1H), 7.56-7.45 (m, 2H), 7.33-7.29 (m, 1H), 7.27 (d, J=9.0Hz, 1H), 7.21 (dd, J=8.5, 1.0 Hz, 2H), 7.00 (s, 1H), 3.72-3.28 (m, 2H),1.33-1.14 (m, 1H), 0.58-0.46 (m, 2H), 0.43-0.32 (m, 2H).

Example 991-(4-(tert-Butylamino)-7-phenoxyquinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 77using 3-phenoxyaniline in step A and 2-methylpropan-2-amine in step D.MS (ESI): mass calcd. for C₂₂H₂₁N₅O₃, 403.2; m/z found, 404.2 [M+H]⁺. ¹HNMR (600 MHz, DMSO-d₆): 8.87 (d, J=0.7 Hz, 1H), 8.51 (d, J=9.1 Hz, 1H),8.11 (d, J=0.6 Hz, 1H), 7.83 (s, 1H), 7.56-7.44 (m, 2H), 7.32-7.28 (m,1H), 7.24 (dd, J=9.1, 2.6 Hz, 1H), 7.22-7.18 (m, 2H), 6.97 (d, J=2.5 Hz,1H), 1.61 (s, 9H).

Example 1001-(7-Fluoro-6-(cyclohexyloxy)-4-morpholinoquinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 1steps B through F using 3-fluoro-4-cyclohexyloxyaniline in step B andmorpholine in step E. MS (ESI): mass calcd. for C₂₂H₂₄FN₅O₄, 441.5; m/zfound, 442.3 [M+H]+. 1H NMR (400 MHz, DMSO-d₆): 12.68 (s, 1H), 9.00 (s,1H), 8.10 (s, 1H), 7.68 (d, J=12.0 Hz, 1H), 7.49 (d, J=9.1 Hz, 1H), 4.58(s, 1H), 3.87 (s, 4H), 3.82 (s, 4H), 1.97 (s, 2H), 1.74 (s, 2H),1.65-1.29 (m, 6H).

Example 1011-(7-fluoro-6-(cyclohexyloxy)-4-(dimethylamino)quinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 1steps B through F using 3-fluoro-4-cyclohexyloxyaniline in step B anddimethylamine in step E. MS (ESI): mass calcd. for C₂₀H₂₂FN₅O₃, 399.4;m/z found, 400.1 [M+H]+. 1H NMR (400 MHz, DMSO-d₆): 12.77 (s, 1H), 8.97(s, 1H), 8.08 (s, 1H), 7.74 (d, J=8.7 Hz, 1H), 7.59 (d, J=11.7 Hz, 1H),4.56 (s, 1H), 3.43 (s, 6H), 1.98 (s, 2H), 1.74 (s, 2H), 1.64-1.25 (m,6H).

Example 1021-(7-fluoro-6-(cyclohexyloxy)-4-(pyrrolidin-1-yl)quinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 1steps B through F using 3-fluoro-4-cyclohexyloxyaniline in step B anddiethylamine in step E. MS (ESI): mass calcd. for C₂₂H₂₆FN₅O₃, 427.5;m/z found, 428.2 [M+H]+. 1H NMR (400 MHz, DMSO-d₆): 12.78 (s, 1H), 8.92(s, 1H), 8.10 (s, 1H), 7.62 (d, J=12.1 Hz, 1H), 7.48 (d, J=8.8 Hz, 1H),4.49 (s, 1H), 3.79 (q, J=6.4 Hz, 4H), 2.03 (s, 2H), 1.76 (s, 2H),1.64-1.26 (m, 12H).

Example 1031-(7-fluoro-6-(cyclohexyloxy)-4-(pyrrolidin-1-yl)quinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 1steps B through F using 3-fluoro-4-cyclohexyloxyaniline in step B andpyrrolidine in step E. MS (ESI): mass calcd. for C₂₂H₂₄FN₅O₃, 425.5; m/zfound, 426.1 [M+H]+. 1H NMR (400 MHz, DMSO-d₆): 12.73 (s, 1H), 8.96 (s,1H), 8.07 (s, 1H), 7.84 (d, J=9.1 Hz, 1H), 7.56 (d, J=12.1 Hz, 1H), 4.53(s, 1H), 3.98 (s, 4H), 2.01 (s, 6H), 1.74 (s, 2H), 1.63-1.27 (m, 6H).

Example 1041-(7-fluoro-6-(cyclohexyloxy)-4-(ethyl(methyl)amino)quinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 1steps B through F using 3-fluoro-4-cyclohexyloxyaniline in step B andN-ethyl-N-methylamine in step E. MS (ESI): mass calcd. for C₂₁H₂₄FN₅O₃,413.5; m/z found, 414.1 [M+H]+. 1H NMR (400 MHz, DMSO-d₆): 12.81 (5,1H), 8.94 (5, 1H), 8.08 (5, 1H), 7.64-7.58 (m, 2H), 4.53 (5, 1H), 3.80(q, J=6.5 Hz, 2H), 3.39 (5, 3H), 2.00 (5, 2H), 1.74 (5, 2H), 1.64-1.26(m, 9H).

Example 1051-(7-fluoro-6-(cyclohexyloxy)-4-(cyclopropylamino)quinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 1steps B through F using 3-fluoro-4-cyclohexyloxyaniline in step B andcyclopropylamine in step E. MS (ESI): mass calcd. for O₂₁H₂₂FN₅O₃,411.4; m/z found, 412.2 [M+H]+. 1H NMR (400 MHz, DMSO-d₆): 8.96 (s, 1H),8.61 (5, 1H), 8.03 (5, 1H), 7.94 (d, J=8.9 Hz, 1H), 7.55 (d, J=12.1 Hz,1H), 4.55 (5, 1H), 3.19-3.07 (m, 1H), 1.95 (5, 2H), 1.74 (5, 2H),1.64-1.26 (m, 6H), 0.97-0.85 (m, 2H), 0.77-0.67 (m, 2H).

Examples 106-135 are prophetic Examples which may be synthesized usingthe general schemes provided above.

Example 1061-(6-Benzyl-7-fluoro-4-morpholinoquinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The above compound may be made analogous to Example 1 using ethyl1-(6-benzyl-7-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylatein step D and morpholine in step E. MS (ESI): predicted mass calcd. forC₂₃H₂₀FN₅O₃, 433.2

Example 1071-(6-Benzyl-4-(dimethylamino)-7-fluoroquinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The above compound may be made analogous to Example 1 using ethyl1-(6-benzyl-7-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylatein step D and dimethylamine in step E. MS (ESI): predicted mass calcd.for C₂₁H₁₈FN₅O₂, 391.1

Example 1081-(6-Benzyl-4-(diethylamino)-7-fluoroquinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The above compound may be made analogous to Example 1 using ethyl1-(6-benzyl-7-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylatein step D and diethylamine in step E. MS (ESI): predicted mass calcd.for C₂₃H₂₂FN₅O₂, 419.2

Example 1091-(6-Benzyl-7-fluoro-4-(pyrrolidin-1-yl)quinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The above compound may be made analogous to Example 1 using ethyl1-(6-benzyl-7-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylatein step D and pyrrolidine in step E. MS (ESI): predicted mass calcd. forC₂₃H₂₀FN₅O₂, 417.2

Example 1101-(6-Benzyl-4-(ethyl(methyl)amino)-7-fluoroquinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The above compound may be made analogous to Example 1 using ethyl1-(6-benzyl-7-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylatein step D and N-methylethanamine in step E. MS (ESI): predicted masscalcd. for C₂₂H₂₀FN₅O₂, 405.2

Example 1111-(6-Benzyl-4-(cyclopropylamino)-7-fluoroquinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The above compound may be made analogous to Example 1 using ethyl1-(6-benzyl-7-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylatein step D and cyclopropyl amine in step E.MS (ESI): predicted masscalcd. for C₂₂H₁₈FN₅O₂, 403.1

Example 1121-(6-((2,6-Dimethylbenzyl)amino)-7-fluoro-4-morpholinoquinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The above compound may be made analogous to Example 1 using ethyl1-(6-((2,6-dimethylbenzyl)amino)-7-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylatein step D and morpholine in step E. MS (ESI): predicted mass calcd. forC₂₅H₂₅FN₆O₃, 476.2

Example 1131-(4-(Dimethylamino)-6-((2,6-dimethylbenzyl)amino)-7-fluoroquinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The above compound may be made analogous to Example 1 using ethyl1-(6-((2,6-dimethylbenzyl)amino)-7-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylatein step D and dimethylamine in step E. MS (ESI): predicted mass calcd.for C₂₃H₂₃FN₆O₂, 434.2

Example 1141-(4-(Diethylamino)-6-(2,6-dimethylbenzyl)amino)-7-fluoroquinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The above compound may be made analogous to Example 1 using ethyl1-(6-((2,6-dimethylbenzyl)amino)-7-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylatein step D and diethylamine in step E. MS (ESI): predicted mass calcd.for C₂₅H₂₇FN₆O₂, 462.2

Example 115 11-(6-((2,6-Dimethylbenzyl)amino)-7-fluoro-4-(pyrrolidin-1-yl)quinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The above compound may be made analogous to Example 1 using ethyl1-(6-((2,6-dimethylbenzyl)amino)-7-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylatein step D and pyrrolidine in step E. MS (ESI): predicted mass calcd. forC₂₅H₂₅FN₆O₂, 460.2

Example 1161-(6-((2,6-Dimethylbenzyl)amino)-4-(ethyl(methyl)amino)-7-fluoroquinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The above compound may be made analogous to Example 1 using ethyl1-(6-((2,6-dimethylbenzyl)amino)-7-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylatein step D and N-methylethanamine in step E. MS (ESI): predicted masscalcd. for C₂₄H₂₅FN₆O₂, 448.2

Example 1171-(4-(Cyclopropylamino)-6-((2,6-dimethylbenzyl)amino)-7-fluoroquinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The above compound may be made analogous to Example 1 using ethyl1-(6-((2,6-dimethylbenzyl)amino)-7-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylatein step D and cyclopropyl amine in step E. MS (ESI): predicted masscalcd. for C₂₄H₂₃FN₆O₂, 446.2

Example 1181-(7-Fluoro-4-morpholino-6-(o-tolyl)quinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The above compound may be made analogous to Example 1 using ethyl1-(7-fluoro-4-oxo-6-(o-tolyl)-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylatein step D and morpholine in step E. MS (ESI): predicted mass calcd. forC₂₃H₂₀FN₅O₃, 433.2

Example 1191-(4-(Dimethylamino)-7-fluoro-6-(o-tolyl)quinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The above compound may be made analogous to Example 1 using ethyl1-(7-fluoro-4-oxo-6-(o-tolyl)-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylatein step D and dimethylamine in step E.MS (ESI): predicted mass calcd.for C₂₁H₁₈FN₅O₂, 391.1

Example 1201-(4-(Diethylamino)-7-fluoro-6-(o-tolyl)quinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The above compound may be made analogous to Example 1 using ethyl1-(7-fluoro-4-oxo-6-(o-tolyl)-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylatein step D and diethylamine in step E. MS (ESI): predicted mass calcd.for C₂₃H₂₂FN₅O₂, 419.2

Example 1211-(7-Fluoro-4-(pyrrolidin-1-yl)-6-(o-tolyl)quinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The above compound may be made analogous to Example 1 using ethyl1-(7-fluoro-4-oxo-6-(o-tolyl)-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylatein step D and pyrrolidine in step E. MS (ESI): predicted mass calcd. forC₂₃H₂₀FN₅O₂, 417.2

Example 1221-(4-(Ethyl(methyl)amino)-7-fluoro-6-(o-tolyl)quinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The above compound may be made analogous to Example 1 using ethyl1-(7-fluoro-4-oxo-6-(o-tolyl)-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylatein step D and N-methylethanamine in step E. MS (ESI): predicted masscalcd. for C₂₂H₂₀FN₅O₂, 405.2

Example 1231-(4-(Cyclopropylamino)-7-fluoro-6-(o-tolyl)quinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The above compound may be made analogous to Example 1 using ethyl1-(7-fluoro-4-oxo-6-(o-tolyl)-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylatein step D and cyclopropyl amine in step E. MS (ESI): predicted masscalcd. for C₂₂H₁₈FN₅O₂, 403.1

Example 1241-(7-Fluoro-6-isopropyl-4-morpholinoquinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The above compound may be made analogous to Example 1 using ethyl1-(7-fluoro-6-isopropyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylatein step D and morpholine in step E. MS (ESI): predicted mass calcd. forC₁₉H₂₀FN₅O₃, 385.2

Example 1251-(4-(Dimethylamino)-7-fluoro-6-isopropylquinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The above compound may be made analogous to Example 1 using ethyl1-(7-fluoro-6-isopropyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylatein step D and dimethylamine in step E. MS (ESI): predicted mass calcd.for C₁₇H₁₈FN₅O₂, 343.1

Example 1261-(4-(Diethylamino)-7-fluoro-6-isopropylquinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The above compound may be made analogous to Example 1 using ethyl1-(7-fluoro-6-isopropyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylatein step D and diethylamine in step E. MS (ESI): predicted mass calcd.for C₁₉H₂₂FN₅O₂, 371.2

Example 1271-(7-Fluoro-6-isopropyl-4-(pyrrolidin-1-yl)quinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The above compound may be made analogous to Example 1 using ethyl1-(7-fluoro-6-isopropyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylatein step D and pyrrolidine in step E. MS (ESI): predicted mass calcd. forC₁₉H₂₀FN₅O₂, 369.2

Example 1281-(4-(Ethyl(methyl)amino)-7-fluoro-6-isopropylquinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The above compound may be made analogous to Example 1 using ethyl1-(7-fluoro-6-isopropyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylatein step D and N-methylethanamine in step E. MS (ESI): predicted masscalcd. for C₁₈H₂₀FN₅O₂, 357.2

Example 1291-(4-(Cyclopropylamino)-7-fluoro-6-isopropylquinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The above compound may be made analogous to Example 1 using ethyl1-(7-fluoro-6-isopropyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylatein step D and cyclopropyl amine in step E. MS (ESI): predicted masscalcd. for C₁₈H₁₈FN₅O₂, 355.1

Example 1301-(7-Fluoro-4-morpholino-6-(piperidin-1-yl)quinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The above compound may be made analogous to Example 1 using ethyl1-(7-fluoro-4-oxo-6-(piperidin-1-yl)-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylatein step D and morpholine in step E. MS (ESI): predicted mass calcd. forC₂₁H₂₃FN₆O₃, 426.2

Example 1311-(4-(Dimethylamino)-7-fluoro-6-(piperidin-1-yl)quinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The above compound may be made analogous to Example 1 using ethyl1-(7-fluoro-4-oxo-6-(piperidin-1-yl)-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylatein step D and dimethylamine in step E. MS (ESI): predicted mass calcd.for C₁₉H₂₁FN₆O₂, 384.2

Example 1321-(4-(Diethylamino)-7-fluoro-6-(piperidin-1-yl)quinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The above compound may be made analogous to Example 1 using ethyl1-(7-fluoro-4-oxo-6-(piperidin-1-yl)-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylatein step D and diethylamine in step E. MS (ESI): predicted mass calcd.for O₂₁H₂₅FN₆O₂, 412.2

Example 1331-(7-Fluoro-6-(piperidin-1-yl)-4-(pyrrolidin-1-yl)quinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The above compound may be made analogous to Example 1 using ethyl1-(7-fluoro-4-oxo-6-(piperidin-1-yl)-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylatein step D and pyrrolidine in step E. MS (ESI): predicted mass calcd. forC₂₁H₂₃FN₆O₂, 410.2

Example 1341-(4-(Ethyl(methyl)amino)-7-fluoro-6-(piperidin-1-yl)quinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The above compound may be made analogous to Example 1 using ethyl1-(7-fluoro-4-oxo-6-(piperidin-1-yl)-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylatein step D and N-methylethanamine in step E. MS (ESI): predicted masscalcd. for C₂₀H₂₃FN₆O₂, 398.2

Example 1351-(4-(Cyclopropylamino)-7-fluoro-6-(piperidin-1-yl)quinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The above compound may be made analogous to Example 1 using ethyl1-(7-fluoro-4-oxo-6-(piperidin-1-yl)-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylatein step D and cyclopropylamine in step E. MS (ESI): predicted masscalcd. for C₂₀H₂₁FN₆O₂, 396.2

Example 1361-(7-chloro-6-(cyclohexyloxy)-4-morpholinoquinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 1steps B through F using 3-chloro-4-cyclohexyloxyaniline in step B andmorpholine in step E. MS (ESI): mass calcd. for C₂₂H₂₄ClN₅O₄, 457.9; m/zfound, 458.1 [M+H]+. 1H NMR (400 MHz, DMSO-d₆): 8.88 (s, 1H), 8.01 (s,1H), 7.94 (s, 1H), 7.43 (s, 1H), 4.65 (s, 1H), 3.87 (s, 4H), 3.83 (s,4H), 1.94 (s, 2H), 1.75 (s, 2H), 1.70-1.33 (m, 6H).

Example 1371-(7-chloro-6-(cyclohexyloxy)-4-(dimethylamino)quinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 1steps B through F using 3-chloro-4-cyclohexyloxyaniline in step B anddimethylamine in step E. MS (ESI): mass calcd. for C₂₀H₂₂ClN₅O₃, 415.9;m/z found, 416.1 [M+H]+. 1H NMR (400 MHz, DMSO-d₆): 12.77 (s, 1H), 8.98(s, 1H), 8.08 (s, 1H), 7.88 (s, 1H), 7.69 (s, 1H), 4.64 (s, 1H), 3.44(s, 6H), 1.95 (s, 2H), 1.83-1.35 (m, 8H).

Example 1381-(7-chloro-6-(cyclohexyloxy)-4-(diethylamino)quinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 1steps B through F using 3-chloro-4-cyclohexyloxyaniline in step B anddiethylamine in step E. MS (ESI): mass calcd. for C₂₂H₂₆ClN₅O₃, 443.9;m/z found, 444.2 [M+H]+. 1H NMR (400 MHz, DMSO-d₆): 12.77 (s, 1H), 8.91(s, 1H), 8.09 (s, 1H), 7.89 (s, 1H), 7.43 (s, 1H), 4.54 (s, 1H), 3.80(q, J=6.6 Hz, 4H), 1.99 (s, 2H), 1.77 (s, 2H), 1.68-1.50 (m, 3H),1.48-1.33 (m, 9H).

Example 1391-(7-chloro-6-(cyclohexyloxy)-4-(pyrrolidin-1-yl)quinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 1steps B through F using 3-chloro-4-cyclohexyloxyaniline in step B andpyrrolidine in step E. MS (ESI): mass calcd. for C₂₂H₂₄ClN₅O₃, 441.9;m/z found, 442.2 [M+H]+. 1H NMR (400 MHz, DMSO-d₆): 8.96 (s, 1H), 8.07(s, 1H), 7.84 (s, 1H), 7.78 (s, 1H), 4.61 (s, 1H), 3.99 (s, 4H),2.10-1.88 (m, 6H), 1.83-1.32 (m, 8H).

Example 1401-(7-chloro-6-(cyclohexyloxy)-4-(ethyl(methyl)amino)quinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 1steps B through F using 3-chloro-4-cyclohexyloxyaniline in step B andN-ethyl-N-methylamine in step E. MS (ESI): mass calcd. for C₂₁H₂₄ClN₅O₃,429.9; m/z found, 430.1 [M+H]+. 1H NMR (400 MHz, DMSO-d₆): 8.94 (s, 1H),8.08 (s, 1H), 7.86 (s, 1H), 7.56 (s, 1H), 4.65-4.54 (m, 1H), 3.81 (q,J=7.5 Hz, 2H), 3.40 (s, 3H), 1.96 (s, 2H), 1.75 (s, 2H), 1.68-1.36 (m,9H).

Example 1411-(7-chloro-6-(cyclohexyloxy)-4-(cyclopropylamino)quinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 1steps B through F using 3-chloro-4-cyclohexyloxyaniline in step B andcyclopropylamine in step E. MS (ESI): mass calcd. for O₂₁H₂₂ClN₅O₃,428.1; m/z found, 442.2 [M+H]+. 1H NMR (400 MHz, DMSO-d₆): 12.75 (s,1H), 9.01 (s, 1H), 8.68 (s, 1H), 8.09 (s, 1H), 7.88 (5, 1H), 7.84 (5,1H), 4.65 (5, 1H), 3.17 (5, 1H), 1.91 (5, 2H), 1.76 (5, 2H), 1.69-1.37(m, 6H), 0.95-0.89 (m, 2H), 0.73 (s, 2H).

Examples 142-159 are prophetic Examples which may be synthesized usingthe general schemes provided above.

Example 1421-(6-Benzyl-7-chloro-4-morpholinoquinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The above compound may be made analogous to Example 1 using ethyl1-(6-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylatein step D and morpholine in step E. MS (ESI): predicted mass calcd. forC₂₃H₂₀ClN₅O₃, 449.9

Example 1431-(6-Benzyl-4-(dimethylamino)-7-chloroquinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The above compound may be made analogous to Example 1 using ethyl1-(6-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylatein step D and dimethylamine in step E. MS (ESI): predicted mass calcd.for C₂₁H₁₈ClN₅O₂, 407.9

Example 1441-(6-Benzyl-4-(diethylamino)-7-chloroquinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The above compound may be made analogous to Example 1 using ethyl1-(6-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylatein step D and diethylamine in step E. MS (ESI): predicted mass calcd.for C₂₃H₂₂ClN₅O₂, 435.9

Example 1451-(6-Benzyl-7-chloro-4-(pyrrolidin-1-yl)quinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The above compound may be made analogous to Example 1 using ethyl1-(6-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylatein step D and pyrrolidine in step E. MS (ESI): predicted mass calcd. forC₂₃H₂₀ClN₅O₂, 433.9

Example 1461-(6-Benzyl-4-(ethyl(methyl)amino)-7-chloroquinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The above compound may be made analogous to Example 1 using ethyl1-(6-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylatein step D and N-methylethanamine in step E. MS (ESI): predicted masscalcd. for C₂₂H₂₀ClN₅O₂, 421.9

Example 1471-(6-Benzyl-4-(cyclopropylamino)-7-chloroquinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The above compound may be made analogous to Example 1 using ethyl1-(6-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylatein step D and cyclopropyl amine in step E.MS (ESI): predicted masscalcd. for C₂₂H₁₈ClN₅O₂, 419.9

Example 1481-(6-((2,6-Dimethylbenzyl)amino)-7-chloro-4-morpholinoquinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The above compound may be made analogous to Example 1 using ethyl1-(6-((2,6-dimethylbenzyl)amino)-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylatein step D and morpholine in step E. MS (ESI): predicted mass calcd. forC₂₅H₂₅ClN₆O₃, 492.9

Example 1491-(4-(Dimethylamino)-6-((2,6-dimethylbenzyl)amino)-7-chloroquinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The above compound may be made analogous to Example 1 using ethyl1-(6-((2,6-dimethylbenzyl)amino)-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylatein step D and dimethylamine in step E. MS (ESI): predicted mass calcd.for C₂₃H₂₃ClN₆O₂, 450.9

Example 1501-(4-(Diethylamino)-6-((2,6-dimethylbenzyl)amino)-7-chloroquinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The above compound may be made analogous to Example 1 using ethyl1-(6-((2,6-dimethylbenzyl)amino)-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylatein step D and diethylamine in step E. MS (ESI): predicted mass calcd.for C₂₅H₂₇ClN₆O₂, 479.0

Example 1511-(6-((2,6-Dimethylbenzyl)amino)-7-chloro-4-(pyrrolidin-1-yl)quinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The above compound may be made analogous to Example 1 using ethyl1-(6-((2,6-dimethylbenzyl)amino)-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylatein step D and pyrrolidine in step E. MS (ESI): predicted mass calcd. forC₂₅H₂₅ClN₆O₂, 479.0

Example 1521-(6-((2,6-Dimethylbenzyl)amino)-4-(ethyl(methyl)amino)-7-chloroquinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The above compound may be made analogous to Example 1 using ethyl1-(6-((2,6-dimethylbenzyl)amino)-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylatein step D and N-methylethanamine in step E. MS (ESI): predicted masscalcd. for C₂₄H₂₅ClN₆O₂, 464.9

Example 1531-(4-(Cyclopropylamino)-6-((2,6-dimethylbenzyl)amino)-7-chloroquinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The above compound may be made analogous to Example 1 using ethyl1-(6-((2,6-dimethylbenzyl)amino)-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylatein step D and cyclopropyl amine in step E. MS (ESI): predicted masscalcd. for C₂₄H₂₃ClN₆O₂, 462.9

Example 1541-(7-Chloro-4-morpholino-6-(o-tolyl)quinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The above compound may be made analogous to Example 1 using ethyl1-(7-chloro-4-oxo-6-(o-tolyl)-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylatein step D and morpholine in step E. MS (ESI): predicted mass calcd. forC₂₃H₂₀ClN₅O₃, 449.9

Example 1551-(4-(Dimethylamino)-7-chloro-6-(o-tolyl)quinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The above compound may be made analogous to Example 1 using ethyl1-(7-chloro-4-oxo-6-(o-tolyl)-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylatein step D and dimethylamine in step E.MS (ESI): predicted mass calcd.for C₂₁H₁₈ClN₅O₂, 407.9

Example 1561-(4-(Diethylamino)-7-chloro-6-(o-tolyl)quinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The above compound may be made analogous to Example 1 using ethyl1-(7-chloro-4-oxo-6-(o-tolyl)-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylatein step D and diethylamine in step E. MS (ESI): predicted mass calcd.for C₂₃H₂₂ClN₅O₂, 435.9

Example 1571-(7-Chloro-4-(pyrrolidin-1-yl)-6-(o-tolyl)quinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The above compound may be made analogous to Example 1 using ethyl1-(7-chloro-4-oxo-6-(o-tolyl)-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylatein step D and pyrrolidine in step E. MS (ESI): predicted mass calcd. forC₂₃H₂₀ClN₅O₂, 433.9

Example 1581-(4-(Ethyl(methyl)amino)-7-chloro-6-(o-tolyl)quinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The above compound may be made analogous to Example 1 using ethyl1-(7-chloro-4-oxo-6-(o-tolyl)-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylatein step D and N-methylethanamine in step E. MS (ESI): predicted masscalcd. for C₂₂H₂₀ClN₅O₂, 421.9

Example 1591-(4-(Cyclopropylamino)-7-chloro-6-(o-tolyl)quinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The above compound may be made analogous to Example 1 using ethyl1-(7-chloro-4-oxo-6-(o-tolyl)-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylatein step D and cyclopropyl amine in step E. MS (ESI): predicted masscalcd. for C₂₂H₁₈ClN₅O₂, 419.9

Example 1601-(7-chloro-6-isopropyl-4-morpholinoquinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 1steps B through F using 3-chloro-4-isopropylaniline in step B andmorpholine in step E. MS (ESI): mass calcd. for C₁₉H₂₀ClN₅O₃, 401.9; m/zfound, 402.1 [M+H]+. 1H NMR (400 MHz, DMSO-d₆): 12.77 (s, 1H), 9.02 (s,1H), 8.11 (s, 1H), 7.88 (s, 2H), 3.97 (s, 4H), 3.81 (s, 4H), 3.33 (s,1H), 1.31 (d, J=6.8 Hz, 6H).

Example 1611-(7-chloro-4-(dimethylamino)-6-isopropylquinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 1steps B through F using 3-chloro-4-isopropylaniline in step B anddimethylamine in step E. MS (ESI): mass calcd. for C₁₇H₁₈ClN₅O₂, 359.8;m/z found, 360.0 [M+H]+. 1H NMR (400 MHz, DMSO-d₆): 9.01 (s, 1H), 8.12(s, 1H), 8.11 (s, 1H), 7.82 (s, 1H), 3.49 (s, 6H), 3.39 (dt, J=14.1, 7.2Hz, 1H), 1.32 (d, J=6.8 Hz, 6H).

Example 1621-(7-chloro-4-diethylamino-6-isopropylquinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 1steps B through F using 3-chloro-4-isopropylaniline in step B anddiethylamine in step E. MS (ESI): mass calcd. for C₁₉H₂₂ClN₅O₂, 387.9;m/z found, 388.1 [M+H]+. 1H NMR (400 MHz, DMSO-d₆): 8.94 (s, 1H), 8.13(s, 1H), 7.91 (s, 1H), 7.83 (s, 1H), 3.84 (q, J=6.7 Hz, 4H), 3.49-3.31(m, 1H), 1.43 (t, J=6.7 Hz, 6H), 1.31 (d, J=6.7 Hz, 6H).

Example 1631-(7-chloro-4-(pyrrolidin-1-yl)-6-isopropylquinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 1steps B through F using 3-chloro-4-isopropylaniline in step B andpyrrolidine in step E. MS (ESI): mass calcd. for C₁₉H₂₀ClN₅O₂, 385.9;m/z found, 386.1 [M+H]+. 1H NMR (400 MHz, DMSO-d₆): 8.98 (s, 1H), 8.19(s, 1H), 8.08 (s, 1H), 7.78 (s, 1H), 4.01 (s, 4H), 3.45-3.33 (m, 1H),2.03 (s, 4H), 1.32 (d, J=6.8 Hz, 6H).

Example 1641-(7-chloro-4-(ethyl(methyl)amino)-6-isopropylquinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 1steps B through F using 3-chloro-4-isopropylaniline in step B andN-ethyl-N-methylamine in step E. MS (ESI): mass calcd. for C₁₈H₂₀ClN₅O₂,373.9; m/z found, 374.1 [M+]+. 1H NMR (400 MHz, DMSO-d₆): 8.99 (s, 1H),8.14 (s, 1H), 8.05 (s, 1H), 7.84 (s, 1H), 3.88 (q, J=7.1 Hz, 2H), 3.48(s, 3H), 3.40 (dt, J=13.3, 6.8 Hz, 1H), 1.41 (t, J=6.9 Hz, 3H), 1.32 (d,J=6.8 Hz, 6H).

Example 1651-(7-chloro-4-(cyclopropylamino)-6-isopropylquinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 1steps B through F using 3-chloro-4-isopropylaniline in step B andcyclopropylamine in step E. MS (ESI): mass calcd. for C₁₈H₁₈ClN₅O₂,371.8; m/z found, 372.1 [M+H]+. 1H NMR (400 MHz, DMSO-d₆): 12.75 (s,1H), 9.04 (s, 1H), 8.87 (s, 1H), 8.27 (s, 1H), 8.11 (s, 1H), 7.78 (s,1H), 3.42-3.33 (m, 1H), 3.21 (s, 1H), 1.32 (d, J=6.6 Hz, 6H), 0.93-0.90(m, 2H), 0.76 (br s, 2H).

Examples 166-171 are prophetic Examples which may be synthesized usingthe general schemes provided above.

Example 1661-(7-Chloro-4-morpholino-6-(piperidin-1-yl)quinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The above compound may be made analogous to Example 1 using ethyl1-(7-chloro-4-oxo-6-(piperidin-1-yl)-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylatein step D and morpholine in step E. MS (ESI): predicted mass calcd. forC₂₁H₂₃ClN₆O₃, 442.9

Example 1671-(4-(Dimethylamino)-7-chloro-6-(piperidin-1-yl)quinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The above compound may be made analogous to Example 1 using ethyl1-(7-chloro-4-oxo-6-(piperidin-1-yl)-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylatein step D and dimethylamine in step E. MS (ESI): predicted mass calcd.for C₁₉H₂₁ClN₆O₂, 400.9

Example 1681-(4-(Diethylamino)-7-chloro-6-(piperidin-1-yl)quinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The above compound may be made analogous to Example 1 using ethyl1-(7-chloro-4-oxo-6-(piperidin-1-yl)-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylatein step D and diethylamine in step E. MS (ESI): predicted mass calcd.for C₂₁H₂₅ClN₆O₂, 428.9

Example 1691-(7-Chloro-6-(piperidin-1-yl)-4-(pyrrolidin-1-yl)quinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The above compound may be made analogous to Example 1 using ethyl1-(7-chloro-4-oxo-6-(piperidin-1-yl)-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylatein step D and pyrrolidine in step E. MS (ESI): predicted mass calcd. forC₂₁H₂₃ClN₆O₂, 410.2

Example 1701-(4-(Ethyl(methyl)amino)-7-chloro-6-(piperidin-1-yl)quinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The above compound may be made analogous to Example 1 using ethyl1-(7-chloro-4-oxo-6-(piperidin-1-yl)-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylatein step D and N-methylethanamine in step E. MS (ESI): predicted masscalcd. for C₂₀H₂₃ClN₆O₂, 414.9

Example 1711-(4-(Cyclopropylamino)-7-chloro-6-(piperidin-1-yl)quinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The above compound may be made analogous to Example 1 using ethyl1-(7-chloro-4-oxo-6-(piperidin-1-yl)-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylatein step D and cyclopropylamine in step E. MS (ESI): predicted masscalcd. for C₂₀H₂₁ClN₆O₂, 412.9

Example 1721-(6-(cyclohexyloxy)-4-morpholinoquinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 1steps B through F using 4-cyclohexyloxyaniline in step B and morpholinein step E. MS (ESI): mass calcd. for C₂₂H₂₅N₅O₄, 423.5; m/z found, 424.2[M+H]+. 1H NMR (400 MHz, DMSO-d₆): 12.75 (s, 1H), 9.01 (s, 1H), 8.10 (s,1H), 7.81 (d, J=9.2 Hz, 1H), 7.56 (dd, J=9.1, 2.3 Hz, 1H), 7.30 (s, 1H),4.52 (s, 1H), 3.84 (s, 8H), 1.97 (s, 2H), 1.75 (s, 2H), 1.62-1.22 (m,6H).

Example 1731-(6-(cyclohexyloxy)-4-(dimethylamino)quinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 1steps B through F using 4-cyclohexyloxyaniline in step B anddimethylamine in step E. MS (ESI): mass calcd. for C₂₀H₂₃N₅O₃, 381.4;m/z found, 382.2 [M+H]+. 1H NMR (400 MHz, DMSO-d₆): 12.80 (s, 1H), 8.93(s, 1H), 8.04 (s, 1H), 7.72 (d, J=9.0 Hz, 1H), 7.58-7.45 (m, 2H), 4.50(s, 1H), 3.42 (s, 6H), 1.97 (s, 2H), 1.74 (s, 2H), 1.63-1.22 (m, 6H).

Example 1741-(6-(cyclohexyloxy)-4-(diethylamino)quinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 1steps B through F using 4-cyclohexyloxyaniline in step B anddiethylamine in step E. MS (ESI): mass calcd. for C₂₂H₂₇N₅O₃, 409.5; m/zfound, 410.2 [M+H]+. 1H NMR (400 MHz, DMSO-d₆): 12.69 (s, 1H), 8.89 (s,1H), 8.07 (s, 1H), 7.72 (d, J=9.1 Hz, 1H), 7.48 (d, J=9.1 Hz, 1H), 7.32(s, 1H), 4.44 (s, 1H), 3.79 (q, J=6.6 Hz, 4H), 2.01 (s, 2H), 1.76 (s,2H), 1.64-1.22 (m, 12H).

Example 1751-(6-(cyclohexyloxy)-4-(pyrrolidin-1-yl)quinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 1steps B through F using 4-cyclohexyloxyaniline in step B and pyrrolidinein step E. MS (ESI): mass calcd. for C₂₂H₂₅N₅O₃, 407.5; m/z found, 408.2[M+]+. 1H NMR (400 MHz, DMSO-d₆): 12.71 (s, 1H), 8.96 (s, 1H), 8.07 (s,1H), 7.71-7.66 (m, 2H), 7.50 (dd, J=9.1, 2.4 Hz, 1H), 4.57-4.41 (m, 1H),3.98 (s, 4H), 2.01 (s, 6H), 1.74 (s, 2H), 1.62-1.21 (m, 6H).

Example 1761-(6-(cyclohexyloxy)-4-(cyclopropylamino)quinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 1steps B through F using 4-cyclohexyloxyaniline in step B andcyclopropylamine in step E. MS (ESI): mass calcd. for C₂₁H₂₃N₅O₃, 393.5;m/z found, 394.2 [M+H]+. 1H NMR (400 MHz, DMSO-d₆): 9.07 (s, 1H), 8.85(s, 1H), 8.17 (s, 1H), 7.86-7.70 (m, 2H), 7.51 (d, J=9.2 Hz, 1H), 4.54(5, 1H), 3.29 (5, 1H), 1.95 (5, 2H), 1.76 (5, 2H), 1.63-1.20 (m, 6H),0.95-0.89 (m, 2H), 0.78 (s, 2H).

Example 1771-(6-(cyclohexyloxy)-4-(ethyl(methyl)amino)quinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 1steps B through F using 4-cyclohexyloxyaniline in step B andN-ethyl-N-methylamine in step E. MS (ESI): mass calcd. for C₂₁H₂₅N₅O₃,395.5; m/z found, 396.2 [M+H]+. 1H NMR (400 MHz, DMSO-d₆): 12.75 (s,1H), 8.91 (s, 1H), 8.04 (s, 1H), 7.72 (d, J=9.1 Hz, 1H), 7.49 (d, J=9.3Hz, 1H), 7.45 (s, 1H), 4.48 (s, 1H), 3.80 (q, J=7.3 Hz, 2H), 3.38 (s,3H), 1.99 (s, 2H), 1.75 (s, 2H), 1.62-1.25 (m, 9H).

Example 1781-(6-benzyl-4-morpholinoquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid

The titled compound was prepared in a manner analogous to EXAMPLE 1steps B through F using 4-benzylaniline in step B and morpholine in stepE. MS (ESI): mass calcd. for C₂₃H₂₁N₅O₃, 415.2; m/z found, 416.2 [M+H]+.1H NMR (400 MHz, DMSO-d₆): 12.75 (s, 1H), 9.00 (s, 1H), 8.09 (s, 1H),7.80-7.68 (m, 3H), 7.36-7.17 (m, 5H), 4.15 (s, 2H), 3.85-3.83 (m, 4H),3.78-3.77 (m, 4H).

Example 1791-(6-benzyl-4-(dimethylamino)quinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 1steps B through F using 4-benzylaniline in step B and dimethylamine instep E. MS (ESI): mass calcd. for C₂₁H₁₉N₅O₂, 373.4; m/z found, 374.2[M+H]+. 1H NMR (400 MHz, DMSO-d₆): 12.71 (s, 1H), 8.97 (s, 1H), 8.07 (s,1H), 8.04 (s, 1H), 7.70-7.63 (m, 2H), 7.31-7.28 (m, 4H), 7.24-7.18 (m,1H), 4.13 (s, 2H), 3.41 (s, 6H).

Example 1801-(6-benzyl-4-(diethylamino)quinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 1steps B through F using 4-benzylaniline in step B and diethylamine instep E. MS (ESI): mass calcd. for C₂₃H₂₃N₅O₂, 401.5; m/z found, 402.2[M+H]+. 1H NMR (400 MHz, DMSO-d₆): 12.76 (s, 1H), 8.89 (s, 1H), 8.07 (s,1H), 7.70 (s, 2H), 7.62 (s, 1H), 7.36-7.21 (m, 5H), 4.14 (s, 2H), 3.70(q, J=6.8 Hz, 4H), 1.24 (t, J=6.9 Hz, 6H).

Example 1811-(6-benzyl-4-(pyrrolidin-1-yl)quinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 1steps B through F using 4-benzylaniline in step B and pyrrolidine instep E. MS (ESI): mass calcd. for C₂₃H₂₁N₅O₂, 399.5; m/z found, 400.3[M+H]+. 1H NMR (400 MHz, DMSO-d₆): 8.88 (s, 1H), 8.14 (s, 1H), 7.99 (s,1H), 7.64 (s, 2H), 7.31-2.29 (m, 4H), 7.23-7.16 (m, 1H), 4.12 (s, 2H),3.93 (s, 4H), 2.00 (s, 4H).

Example 1821-(6-benzyl-4-(cyclopropylamino)quinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 1steps B through F using 4-benzylaniline in step B and cyclopropyl aminein step E. MS (ESI): mass calcd. for C₂₂H₁₉N₅O₂, 385.4; m/z found, 386.1[M+H]+. 1H NMR (400 MHz, DMSO-d₆): 8.96 (s, 1H), 8.76 (d, J=3.6 Hz, 1H),8.31 (s, 1H), 8.01 (s, 1H), 7.66-7.60 (m, 2H), 7.32-7.23 (m, 4H),7.22-7.13 (m, 1H), 4.05 (s, 2H), 3.24-3.18 (m, 1H), 0.92-0.82 (m, 2H),0.81-0.71 (m, 2H).

Example 1831-(6-benzyl-4-(ethyl(methyl)amino)quinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 1steps B through F using 4-benzylaniline in step B andN-ethyl-N-methylamine in step E. MS (ESI): mass calcd. for C₂₂H₂₁N₅O₂,387.4; m/z found, 388.1 [M+H]+. 1H NMR (400 MHz, DMSO-d₆): 8.94 (s, 1H),8.07 (s, 1H), 7.88 (s, 1H), 7.68 (s, 2H), 7.34-7.28 (m, 4H), 7.21 (brs,1H), 4.13 (s, 2H), 3.75 (q, J=6.8 Hz, 2H), 3.36 (s, 3H), 1.26 (t, J=6.9Hz, 3H).

Example 1841-(4-(morpholino)-6-isopropylquinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 1steps B through F using 4-isopropylaniline in step B and morpholine instep E. MS (ESI): mass calcd. for C₁₉H₂₁N₅O₃, 367.4; m/z found, 368.1[M+H]+. 1H NMR (400 MHz, DMSO-d₆): 12.77 (s, 1H), 9.03 (s, 1H), 8.11 (s,1H), 7.80 (s, 3H), 3.92 (s, 4H), 3.82 (s, 4H), 3.11 (dt, J=13.5, 6.7 Hz,1H), 1.29 (d, J=6.8 Hz, 6H).

Example 1851-(4-(dimethylamino)-6-isopropylquinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 1steps B through F using 4-isopropylaniline in step B and dimethylaminein step E. MS (ESI): mass calcd. for C₁₇H₁₉N₅O₂, 325.4; m/z found, 326.2[M+H]+. 1H NMR (400 MHz, DMSO-d₆): 12.66 (s, 1H), 9.00 (s, 1H), 8.08 (s,1H), 8.02 (s, 1H), 7.82-7.69 (m, 2H), 3.45 (s, 6H), 3.10 (dt, J=13.6,6.6 Hz, 1H), 1.29 (d, J=6.8 Hz, 6H).

Example 1861-(4-(diethylamino)-6-isopropylquinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 1steps B through F using 4-isopropylaniline in step B and diethylamine instep E. MS (ESI): mass calcd. for C₁₉H₁₂₃N₅O₂, 353.4; m/z found, 354.2[M+H]+. 1H NMR (400 MHz, DMSO-d₆): 12.77 (s, 1H), 8.96 (s, 1H), 8.13 (s,1H), 7.78 (t, J=13.6 Hz, 3H), 3.84 (q, J=6.7 Hz, 4H), 3.09 (dt, J=14.0,7.0 Hz, 1H), 1.42 (t, J=6.9 Hz, 6H), 1.30 (d, J=6.9 Hz, 6H).

Example 1871-(6-isopropyl-4-(pyrrolidin-1-yl)quinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 1steps B through F using 4-isopropylaniline in step B and pyrrolidine instep E. MS (ESI): mass calcd. for C₁₉H₂₁N₅O₂, 351.4; m/z found, 352.1[M+H]. 1H NMR (400 MHz, DMSO-d₆): 8.96 (s, 1H), 8.08 (d, J=11.4 Hz, 2H),7.78-7.63 (m, 2H), 3.98 (s, 4H), 3.13-3.05 (m, 1H), 2.02 (s, 4H), 1.29(d, J=6.3 Hz, 6H).

Example 1881-(4-(cyclopropylamino)-6-isopropylquinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 1steps B through F using 4-isopropylaniline in step B andcyclopropylamine in step E. MS (ESI): mass calcd. for C₁₈H₁₉N₅O₂, 337.4;m/z found, 338.1 [M+H]+. 1H NMR (400 MHz, DMSO-d₆): 9.08 (s, 1H), 9.00(s, 1H), 8.25 (s, 1H), 8.16 (s, 1H), 7.80-7.69 (m, 2H), 3.32 (s, 1H),3.04 (dt, J=13.4, 6.7 Hz, 1H), 1.30 (d, J=6.9 Hz, 6H), 1.02-0.76 (m,4H).

Example 1891-(6-isopropyl-4-(ethyl(methyl)amino)quinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 1steps B through F using 4-isopropylaniline in step B andN-ethyl-N-methylamine in step E. MS (ESI): mass calcd. for C₁₈H₂₁N₆O₂,339.4; m/z found, 340.1 [M+H]+. 1H NMR (400 MHz, DMSO-d₆): 9.10 (s, 1H),8.26 (s, 1H), 8.02 (s, 1H), 7.93-7.83 (m, 2H), 3.97 (q, J=6.9 Hz, 2H),3.56 (s, 3H), 3.12 (dt, J=13.7, 6.9 Hz, 1H), 1.40 (t, J=7.0 Hz, 3H),1.29 (d, J=6.9 Hz, 6H).

Examples 190-213 are prophetic Examples which may be synthesized usingthe general schemes provided above.

Example 1901-(6-((2,6-Dimethylbenzyl)amino)-4-morpholinoquinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The above compound may be made analogous to Example 1 using ethyl1-(6-((2,6-dimethylbenzyl)amino)-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylatein step D and morpholine in step E. MS (ESI/CI): predicted massC₂₅H₂₆N₆O₃, 458.2.

Example 1911-(6-((2,6-Dimethylbenzyl)amino)-4-(dimethylamino)quinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The above compound may be made analogous to Example 1 using ethyl1-(6-((2,6-dimethylbenzyl)amino)-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylatein step D and dimethylamine in step E. MS (ESI/CI): predicted massC₂₃H₂₄N₆O₂, 416.20.

Example 1921-(6-((2,6-Dimethylbenzyl)amino)-4-(diethylamino)quinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The above compound may be made analogous to Example 1 using ethyl1-(6-((2,6-dimethylbenzyl)amino)-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylatein step D and diethylamine in step E. MS (ESI/CI): predicted massC₂₅H₂₈N₆O₂, 444.2.

Example 1931-(6-((2,6-Dimethylbenzyl)amino)-4-(pyrrolidin-1-yl)quinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The above compound may be made analogous to Example 1 using ethyl1-(6-((2,6-dimethylbenzyl)amino)-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylatein step D and pyrrolidine in step E. MS (ESI/CI): predicted massC₂₅H₂₆N₆O₂, 442.2.

Example 1941-(6-((2,6-Dimethylbenzyl)amino)-4-(cyclopropylamino)quinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The above compound may be made analogous to Example 1 using ethyl1-(6-((2,6-dimethylbenzyl)amino)-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylatein step D and cyclopropylamine in step E. MS (ESI/CI): predicted massC₂₄H₂₄N₆O₂, 428.2.

Example 1951-(6-((2,6-Dimethylbenzyl)amino)-4-(ethyl(methyl)amino)quinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The above compound may be made analogous to Example 1 using ethyl1-(6-((2,6-dimethylbenzyl)amino)-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylatein step D and N-ethyl-N-methylamine in step E. MS (ESI/CI): predictedmass C₂₄H₂₆N₆O₂, 430.2.

Example 1961-(4-Morpholino-6-(o-tolyl)quinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The above compound may be made analogous to Example 1 using ethyl1-(6-(o-tolyl)-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylatein step D and morpholine in step E. MS (ESI/CI): predicted massC₂₃H₂₁N₅O₃, 415.2.

Example 1971-(4-(Dimethylamino)-6-(o-tolyl)quinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The above compound may be made analogous to Example 1 using ethyl1-(6-(o-tolyl)-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylatein step D and dimethylamine in step E. MS (ESI/CI): predicted massC₂₁H₁₉N₅O₂, 373.2.

Example 1981-(4-(Diethylamino)-6-(o-tolyl)quinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The above compound may be made analogous to Example 1 using ethyl1-(6-(o-tolyl)-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylatein step D and diethylamine in step E. MS (ESI/CI): predicted massC₂₃H₂₃N₅O₂, 401.2.

Example 1991-(4-(Pyrrolidin-1-yl)-6-(o-tolyl)quinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The above compound may be made analogous to Example 1 using ethyl1-(6-(o-tolyl)-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylatein step D and pyrrolidine in step E. MS (ESI/CI): predicted massC₂₃H₂₁N₅O₂, 399.2.

Example 2001-(4-(Cyclopropylamino)-6-(o-tolyl)quinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The above compound may be made analogous to Example 1 using ethyl1-(6-(o-tolyl)-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylatein step D and cyclopropylamine in step E. MS (ESI/CI): predicted massC₂₂H₁₉N₅O₂, 385.2.

Example 2011-(4-(Ethyl(methyl)amino)-6-(o-tolyl)quinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The above compound may be made analogous to Example 1 using ethyl1-(6-(o-tolyl)-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylatein step D and N-ethyl-N-methylamine in step E. MS (ESI/CI): predictedmass C₂₂H₂₁N₅O₂, 387.2.

Example 2021-(4-Morpholino-6-(piperidin-1-yl)quinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The above compound may be made analogous to Example 1 using ethyl1-(6-(piperidin-1-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylatein step D and morpholine in step E. MS (ESI/CI): predicted massC₂₁H₂₄N₆O₃, 408.2.

Example 2031-(4-(Dimethylamino)-6-(piperidin-1-yl)quinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The above compound may be made analogous to Example 1 using ethyl1-(6-(piperidin-1-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylatein step D and dimethylamine in step E. MS (ESI/CI): predicted massC₁₉H₂₂N₆O₂, 366.2.

Example 2041-(4-(Diethylamino)-6-(piperidin-1-yl)quinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The above compound may be made analogous to Example 1 using ethyl1-(6-(piperidin-1-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylatein step D and diethylamine in step E. MS (ESI/CI): predicted massO₂₁H₂₆N₆O₂, 394.2.

Example 2051-(6-(Piperidin-1-yl)-4-(pyrrolidin-1-yl)quinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The above compound may be made analogous to Example 1 using ethyl1-(6-(piperidin-1-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylatein step D and pyrrolidine in step E. MS (ESI/CI): predicted massO₂₁H₂₄N₆O₂, 392.2.

Example 2061-(4-(Cyclopropylamino)-6-(piperidin-1-yl)quinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The above compound may be made analogous to Example 1 using ethyl1-(6-(piperidin-1-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylatein step D and cyclopropylamine in step E. MS (ESI/CI): predicted massC₂₀H₂₂N₆O₂, 378.2.

Example 2071-(4-(Ethyl(methyl)amino)-6-(piperidin-1-yl)quinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The above compound may be made analogous to Example 1 using ethyl1-(6-(piperidin-1-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylatein step D and N-ethyl-N-methylamine in step E. MS (ESI/CI): predictedmass C₂₀H₂₄N₆O₂, 380.2.

Example 2081-(6-(2,6-Dimethylphenoxy)-7-methyl-4-morpholinoquinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The above compound may be made analogous to Example 1 using ethyl1-(6-(2,6-dimethylphenoxy)-7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylatein step D and morpholine in step E. MS (ESI/CI): predicted massC₂₅H₂₅N₅O₄, 459.2.

Example 2091-(6-(2,6-Dimethylphenoxy)-7-methyl-4-dimethylaminoquinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The above compound may be made analogous to Example 1 using ethyl1-(6-(2,6-dimethylphenoxy)-7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylatein step D and dimethylamine in step E. MS (ESI/CI): predicted massC₂₃H₂₃N₅O₃, 417.2.

Example 2101-(6-(2,6-Dimethylphenoxy)-7-methyl-4-diethylaminoquinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The above compound may be made analogous to Example 1 using ethyl1-(6-(2,6-dimethylphenoxy)-7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylatein step D and diethylamine in step E. MS (ESI/CI): predicted massC₂₅H₂₇N₅O₃, 445.2.

Example 2111-(6-(2,6-Dimethylphenoxy)-7-methyl-4-(pyrrolidin-1-yl)quinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The above compound may be made analogous to Example 1 using ethyl1-(6-(2,6-dimethylphenoxy)-7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylatein step D and pyrrolidine in step E. MS (ESI/CI): predicted massC₂₅H₂₅N₅O₃, 443.2.

Example 2121-(6-(2,6-Dimethylphenoxy)-7-methyl-4-cyclopropylaminoquinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The above compound may be made analogous to Example 1 using ethyl1-(6-(2,6-dimethylphenoxy)-7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylatein step D and cyclopropylamine in step E. MS (ESI/CI): predicted massC₂₄H₂₃N₅O₃, 429.2.

Example 2131-(6-(2,6-Dimethylphenoxy)-4-(ethyl(methyl)amino)-7-methylquinazolin-2-yl)-1H-pyrazole-4-carboxylicacid

The above compound may be made analogous to Example 1 using ethyl1-(6-(2,6-dimethylphenoxy)-7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylatein step D and N-ethyl-N-methylamine in step E. MS (ESI/CI): predictedmass C₂₅H₂₄N₅O₃, 431.2.

Biological Protocols:

Expression and Purification of PHD2₁₈₁₋₄₁₇

The human PHD2 expression construct containing amino acids 181-417 ofGenBank Accession ID NM_(—)022051 was cloned into a pBAD vector(Invitrogen), incorporating both an N-terminal histidine tag and aSmt3-tag, both of which are cleaved by Ulp1. Protein production wasachieved by expression in BL21 cells grown in Terrific Broth containing100 μg/ml ampicillin. Cell cultures were inoculated at 37° C. and grownto an OD₆₀₀ of 0.8. Cultures were induced with 0.1% arabinose and grownovernight at 20° C. with continuous shaking at 225 rpm. Cells were thenharvested by centrifugation and stored at −80° C. Cell pellets weresuspended in Buffer A (50 mM Tris-HCl pH 7.2, 100 mM NaCl, 100 mML-arginine, 1 mM TCEP, 0.05% (w/v) NP-40, 50 mM imidazole) followed bythe addition of lysozyme and benzonase. Cells were lysed by sonicationand the lysate was cleared by centrifugation (15,000 rpm, 90 min, 4°C.). The protein was purified by nickel affinity chromatography using aHisTrap Crude FF column (GE Healthcare). Samples were eluted in Buffer Awith a 50-200 mM imidazole gradient. Cleavage of the Smt tag with Ulp1protease was achieved via overnight incubation with dialyzing againstBuffer A. The PHD2₁₈₁₋₄₁₇ sample was then passed over a second HisTrapCrude FF column (GE Healthcare) to remove uncleaved protein. Theflow-through was then dialyzed into 50 mM MES pH 6.0, 1 mM TCEP, 5 mMNaCl for ion exchange chromatography on a HiTrap SP Cation Exchangecolumn (GE Healthcare). The PHD2₁₈₁₋₄₁₇ protein was eluted with a 0-0.2M NaCl gradient. Fractions were pooled for further purification by sizeexclusion chromatography over a Superdex 75 Size Exclusion Column (GEHealthcare). Final protein was concentrated to 4 mg/ml and dialyzed in10 mM PIPES pH 7.0, 100 mM NaCl, 0.5 mM TCEP. The protein was determinedto have a purity of >95% by gel electrophoresis.

Enzyme Activity Assay

The PHD enzymatic assay was performed in 0.5 ml of reaction mixturecontaining the following: purified PHD2₁₈₁₋₄₁₇ polypeptide (3 μg),synthetic HIF-1α peptide comprising residues[KNPFSTGDTDLDLEMLAPYIPMDDDFQLRSFDQLS](10 μM, California Peptide ResearchInc., Napa, Calif.), and [5-¹⁴C]-2-oxoglutaric acid (50 mCi/mmol,Moravek Chemicals, Brea, Calif.) in reaction buffer (40 mM Tris-HCl, pH7.5, 0.4 mg/ml catalase, 0.5 mM DTT, 1 mM ascorbate) for 10 minutes.Compounds were pre-incubated for 30 min before starting the reaction(all test compounds were dissolved at 10 mM in 100% DMSO (w/v) and weretested with final compound concentrations at 100 μM in 1% DMSO (w/v)).The reaction was stopped by addition of 50 μl of 70 mM H₃PO₄ and 50 μlof 500 mM NaH₂PO₄, pH 3.2. Detection of [¹⁴C]-succinic acid was achievedby separating from [5-¹⁴C]-2-oxoglutaric acid by incubating the reactionmixture with 100 μl of 0.16 M DNP prepared in 30% perchloric acid. Next,50 μl of unlabeled 20 mM 2-oxoglutaric acid/20 mM succinic acid, servingas carrier for the radioactivity, was added to the mixture, and wasallowed to proceed for 30 minutes at room temperature. The reaction wasthen incubated with 50 μl of 1 M 2-oxoglutaric acid for 30 additionalminutes at room temperature to precipitate the excess DNP. The reactionwas then centrifuged at 2800×g for 10 minutes at room temperature toseparate [¹⁴C]-succinic acid in the supernatant from the precipitated[¹⁴C]-dinitrophenylhydrazone. Fractions of the supernatant (400 μl) werecounted using a beta counter (Beckman Coulter, Fullerton, Calif.).Inhibition of PHD2₁₈₁₋₄₁₇ activity was measured as a decrease in[¹⁴C]-succinic acid production. The IC₅₀ values were estimated byfitting the data to a three-parameter logistic function using GraphPadPrism, version 4.02 (Graph Pad Software, San Diego, Calif.).

Cellular Assay

Hep-3B cells (ATCC, Manassas, Va.) were plated in 96-well plates at20,000 cells per well in 100 μl of DMEM containing 10% fetal bovineserum, 1% non-essential amino acids, 50 IU/mL of penicillin and 50 μg/mLof streptomycin (all cell culture reagents from Invitrogen, Carlsbad,Calif.). Twenty-four hours after plating, compounds were added andincubated for an additional 24 hours. All compounds were tested withfinal compound concentrations at 100 μM. Fifty microliters of thesupernatant was then transferred to a human Hypoxia assay kit(Meso-Scale Discovery, Gaithersburg, Md.). Erythropoietin in thesupernatant was detected according to the manufacturer's instructions asfollows. EPO detection plates were blocked with 3% BSA in PBS overnightand 50 μl of the supernatant was incubated at room temperature in anorbital shaker for 2 h. Twenty-five microliters of 0.5 μg/ml anti-EPOdetection antibody was added for 2 hours at room temperature in anorbital shaker. After 3 washes in PBS, 150 μl of 1× read buffer is addedand the plate is then read on the MSD SECTOR instrument. Data wasanalyzed by determining the percent of EPO secretion in the presence of100 μM compound relative to an assay control compound,7-[(4-Chloro-phenyl)-(5-methyl-isoxazol-3-ylamino)-methyl]-quinolin-8-ol.

Cellular Assay for HIF1-α

Hela cells (ATCC, Manassas, Va.) were plated in 96-well plates at 20,000cells per well in 100 μl of DMEM containing 10% fetal bovine serum, 1%non-essential amino acids, 50 IU/mL of penicillin and 50 μg/mL ofstreptomycin (all cell culture reagents from Invitrogen, Carlsbad,Calif.). 24 hours after plating, changed media to 100 ul of DMEM without10% fetal bovine serum, 1.1 μl of the stock solution for each compoundwas added and incubated for 6 hours. All compounds were tested with afinal compound concentration of 100 μM. The supernatant was removed andthe cells were lysed in 55 μl of MSD lysis buffer containing proteaseinhibitors. 50 μl of the cell lysate was then transferred to a blockedMSD human HIF-1α detection plate (Meso-Scale Discovery, Gaithersburg,Md., as per manufacturers protocol), and incubated at room temperatureon an orbital shaker for 2 hour. After 3 washes in PBS, 25 μl of 20 nManti-HIF1α detection antibody was added and incubated for 1 hour at roomtemperature on an orbital shaker. After 3 washes in PBS, 150 μl of 1×read buffer was added and the plate was then read on a MSD SECTORinstrument. Data was analyzed by determining the percent of HIFstimulation in the presence of 100 μM compound relative to an assaycontrol compound,7-[(4-Chloro-phenyl)-(5-methyl-isoxazol-3-ylamino)-methyl]-quinolin-8-ol.

Results for the compounds tested in these assays are presented in Table1 as an average of results obtained (NT=not tested).

TABLE 1 Cellular % Enzyme EPO % HIF Ex Chemical Name pIC₅₀ StimulationStimulation 1 1-[4-Amino-6-(2,6-dimethyl-phenoxy)-7- 7.2 51 NTfluoro-quinazolin-2-yl]-1H-pyrazole-4- carboxylic acid; 21-[6-(2,6-Dimethyl-phenoxy)-7-fluoro-4- 7.2 10 NTmethylamino-quinazolin-2-yl]-1H- pyrazole-4-carboxylic acid; 31-[4-Dimethylamino-6-(2,6-dimethyl- 7.2 68 NTphenoxy)-7-fluoro-quinazolin-2-yl]-1H- pyrazole-4-carboxylic acid; 41-[6-(2,6-Dimethyl-phenoxy)-7-fluoro-4- 6.9 17 NTpiperidin-1-yl-quinazolin-2-yl]-1H- pyrazole-4-carboxylic acid; 51-[6-(2,6-Dimethyl-phenoxy)-7-fluoro-4- 7.4 25 NTpyrrolidin-1-yl-quinazolin-2-yl]-1H- pyrazole-4-carboxylic acid; 61-[6-(2,6-Dimethyl-phenoxy)-7-fluoro-4- 7.4 22 NTphenylamino-quinazolin-2-yl]-1H- pyrazole-4-carboxylic acid; 71-[4-(2-Chloro-phenylamino)-6-(2,6- 7.2 13 NTdimethyl-phenoxy)-7-fluoro-quinazolin-2- yl]-1H-pyrazole-4-carboxylicacid; 8 1-[6-(2,6-Dimethyl-phenoxy)-7-fluoro-4- 7.2 59 NTpropylamino-quinazolin-2-yl]-1H-pyrazole- 4-carboxylic acid; 9(rac)-1-[6-(2,6-Dimethyl-phenoxy)-7- 7.1 86 NTfluoro-4-(2-methoxy-1-methyl- ethylamino)-quinazolin-2-yl]-1H-pyrazole-4-carboxylic acid; 10 1-[4-(2-Diethylamino-ethylamino)-6-(2,6- 5.9 13 NTdimethyl-phenoxy)-7-fluoro-quinazolin-2- yl]-1H-pyrazole-4-carboxylicacid; 11 1-[6-(2,6-Dimethyl-phenoxy)-4- 7.1  9 NTdibutylamino-7-fluoro-quinazolin-2-yl]-1H- pyrazole-4-carboxylic acid;12 1-[6-(2,6-Dimethyl-phenoxy)-4- 7.4  9 NTdipropylamino-7-fluoro-quinazolin-2-yl]- 1H-pyrazole-4-carboxylic acid;13 1-(4-((Cyclohexylmethyl)amino)-6-(2,6- 6.9 10 NTdimethylphenoxy)-7-fluoroquinazolin-2- yl)-1H-pyrazole-4-carboxylicacid; 14 1-((4-Cyclopropylamino)-6-(2,6- 7.1 86 NTdimethylphenoxy)-7-fluoroquinazolin-2- yl)-1H-pyrazole-4-carboxylicacid; 15 1-((4-Cyclopropanemethylamino)-6-(2,6- 7.2 64 NTdimethylphenoxy)-7-fluoroquinazolin-2- yl)-1H-pyrazole-4-carboxylicacid; 16 1-(6-(2,6-Dimethylphenoxy)-7-fluoro-4- 7.1 71 NT((tetrahydro-2H-pyran-4- yl)amino)quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 17 1-(6-(2,6-Dimethylphenoxy)-7-fluoro-4-(4- 6.7 NT 47methyl-1,4-diazepan-1-yl)quinazolin-2-yl)- 1H-pyrazole-4-carboxylicacid; 18 1-(6-(2,6-Dimethylphenoxy)-7-fluoro-4- 7.0 NT 15thiomorpholinoquinazolin-2-yl)-1H- pyrazole-4-carboxylic acid; 191-(6-(2,6-dimethylphenoxy)-7-fluoro-4-(4- 6.9 NT 140hydroxypiperidin-1-yl)quinazolin-2-yl)-1H- pyrazole-4-carboxylic acid;20 1-(6-(2,6-Dimethylphenoxy)-7-fluoro-4- 7.0 54 NTmorpholinoquinazolin-2-yl)-1H-pyrazole- 4-carboxylic acid; 211-(4-(4-Acetamidopiperidin-1-yl)-6-(2,6- 6.9 NT 62dimethylphenoxy)-7-fluoroquinazolin-2- yl)-1H-pyrazole-4-carboxylicacid; 22 1-(6-Cyclohexyl-4-methylamino- 7.1 48 NTquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 231-[6-Cyclohexyl-4-(2,6-dimethyl- 5.9  7 NTbenzylamino)-quinazolin-2-yl]-1H- pyrazole-4-carboxylic acid; 241-(4-Amino-6-cyclohexylquinazolin-2-yl)- 7.5 36 NT1H-pyrazole-4-carboxylic acid; 25 1-(6-Cyclohexyl-4-(pyrrolidin-1- 6.439 NT yl)quinazolin-2-yl)-1H-pyrazole-4- carboxylic acid; 261-(6-Cyclohexyl-4-(piperidin-1- 7.1 20 NTyl)quinazolin-2-yl)-1H-pyrazole-4- carboxylic acid; 271-(6-Cyclohexyl-4- 7.3 45 NT (diethylamino)quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 28 1-(6-Cyclohexyl-4- 7.3 31 NT(phenylamino)quinazolin-2-yl)-1H- pyrazole-4-carboxylic acid; 291-(4-((2-Chlorophenyl)amino)-6- 7.1 NT 7.8cyclohexylquinazolin-2-yl)-1H-pyrazole-4- carboxylic acid; 301-(4-(4-Cyanopiperidin-1-yl)-6- 6.9 NT 77cyclohexylquinazolin-2-yl)-1H-pyrazole-4- carboxylic acid; 311-(6-Cyclohexyl-4-(4-fluoropiperidin-1- 7.1 NT 34yl)quinazolin-2-yl)-1H-pyrazole-4- carboxylic acid; 321-(6-Cyclohexyl-4- 6.7 49 NT (cyclopropylamino)quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 33 1-(6-Cyclohexyl-4-morpholinoquinazolin-6.8 36 NT 2-yl)-1H-pyrazole-4-carboxylic acid; 34 1-(6-Cyclohexyl-4- 6.920 NT thiomorpholinoquinazolin-2-yl)-1H- pyrazole-4-carboxylic acid; 351-(4-Cyanamido-6-cyclohexylquinazolin- 7.2 67 NT2-yl)-1H-pyrazole-4-carboxylic acid; 36 1-(4-(tert-Butylamino)-6- 6.8 NT23 cyclohexylquinazolin-2-yl)-1H-pyrazole-4- carboxylic acid; 371-(4-(Azepan-1-yl)-6- 7.1 17 NTcyclohexylquinazolin-2-yl)-1H-pyrazole-4- carboxylic acid; 381-(6-Cyclohexyl-4- 7.2 61 NT (dimethylamino)quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 39 1-(6-Cyclohexyl-4- 6.9 NT 6.1((cyclohexylmethyl)amino)quinazolin-2- yl)-1H-pyrazole-4-carboxylicacid; 40 1-(6-Cyclohexyl-4- 6.6 NT 6.7(methylsulfonamido)quinazolin-2-yl)-1H- pyrazole-4-carboxylic acid; 411-(4-(Dimethylamino)-6-phenylquinazolin- 7.2 43 NT2-yl)-1H-pyrazole-4-carboxylic acid; 42 1-(4-(Ethyl(methyl)amino)-6- 7.356 NT phenylquinazolin-2-yl)-1H-pyrazole-4- carboxylic acid; 431-(6-Phenyl-4-(pyrrolidin-1-yl)quinazolin- 7.3 NT 572-yl)-1H-pyrazole-4-carboxylic acid; 441-(6-Phenyl-4-(phenylamino)quinazolin-2- 7.1 NT 22yl)-1H-pyrazole-4-carboxylic acid 451-(6-Phenyl-4-(piperidin-1-yl)quinazolin-2- 7.2  8 NTyl)-1H-pyrazole-4-carboxylic acid; 461-(4-(Diethylamino)-6-phenylquinazolin-2- 7.4 26 NTyl)-1H-pyrazole-4-carboxylic acid; 47 1-(4-((2-Chlorophenyl)amino)-6-6.6 NT 10 phenylquinazolin-2-yl)-1H-pyrazole-4- carboxylic acid; 481-(4-(Azepan-1-yl)-6-phenylquinazolin-2- 7.2 NT 23yl)-1H-pyrazole-4-carboxylic acid; 49 1-(4-((Cyclohexylmethyl)amino)-6-6.9 NT 3.8 phenylquinazolin-2-yl)-1H-pyrazole-4- carboxylic acid; 501-(4-Cyanamido-6-phenylquinazolin-2-yl)- 7.1 NT 9.61H-pyrazole-4-carboxylic acid; 51 1-(4-(Cyclopropylamino)-6- 6.5 NT 40phenylquinazolin-2-yl)-1H-pyrazole-4- carboxylic acid; 521-(4-(tert-Butylamino)-6-phenylquinazolin- 6.5 NT 372-yl)-1H-pyrazole-4-carboxylic acid; 531-(4-Amino-6-phenylquinazolin-2-yl)-1H- 7.0 NT 16 pyrazole-4-carboxylicacid; 54 1-(6-Phenyl-4-thiomorpholinoquinazolin- 6.8 25 NT2-yl)-1H-pyrazole-4-carboxylic acid; 551-(4-(4-Acetamidopiperidin-1-yl)-6- 6.7 NT 28phenylquinazolin-2-yl)-1H-pyrazole-4- carboxylic acid; 561-(6-Phenyl-4-((tetrahydro-2H-pyran-4- 6.2 NT 25yl)amino)quinazolin-2-yl)-1H-pyrazole-4- carboxylic acid; 571-(4-(4-Methyl-1,4-diazepan-1-yl)-6- 6.4 NT 30phenylquinazolin-2-yl)-1H-pyrazole-4- carboxylic acid; 581-(4-Morpholino-6-phenylquinazolin-2-yl)- 6.5 NT 491H-pyrazole-4-carboxylic acid; 59 1-(4-(4-Cyanopiperidin-1-yl)-6- 6.4 NT45 phenylquinazolin-2-yl)-1H-pyrazole-4- carboxylic acid; 601-(6-(4-Chlorophenoxy)-4- 7.3 22 NT (diethylamino)quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 61 1-(6-(4-Chlorophenoxy)-4-(pyrrolidin-1-7.3 96 NT yl)quinazolin-2-yl)-1H-pyrazole-4- carboxylic acid; 621-(6-(4-Chlorophenoxy)-4- 7.0 32 NT(cyclopropylamino)quinazolin-2-yl)-1H- pyrazole-4-carboxylic acid; 631-(6-(4-Chlorophenoxy)-4-(piperidin-1- 7.6 39 NTyl)quinazolin-2-yl)-1H-pyrazole-4- carboxylic acid; 641-(6-(4-Chlorophenoxy)-4- 7.5 NT 1.5((cyclohexylmethyl)amino)quinazolin-2- yl)-1H-pyrazole-4-carboxylicacid; 65 1-(6-(4-chlorophenoxy)-4-(4- 7.4 77 NTcyanopiperidin-1-yl)quinazolin-2-yl)-1H- pyrazole-4-carboxylic acid; 661-(4-(Azepan-1-yl)-6-(4- 7.5 NT 14 chlorophenoxy)quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 67 1-(6-(4-Chlorophenoxy)-4- 7.3 NT 31thiomorpholinoquinazolin-2-yl)-1H- pyrazole-4-carboxylic acid; 681-(6-(4-Chlorophenoxy)-4-((tetrahydro- 6.9 40 NT2H-pyran-4-yl)amino)quinazolin-2-yl)-1H- pyrazole-4-carboxylic acid; 691-(6-(4-Chlorophenoxy)-4- 7.7 23 NT (phenylamino)quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 70 1-(4-(4-Acetamidopiperidin-1-yl)-6-(4-7.1 16 NT chlorophenoxy)quinazolin-2-yl)-1H- pyrazole-4-carboxylic acid;71 1-(6-(4-Chlorophenoxy)-4-(4-methyl-1,4- 6.7 17 NTdiazepan-1-yl)quinazolin-2-yl)-1H- pyrazole-4-carboxylic acid; 721-(4-(tert-Butylamino)-6- 6.7 NT 32phenoxyquinazolin-2-yl)-1H-pyrazole-4- carboxylic acid; 731-(6-Phenoxy-4-(pyrrolidin-1- 7.2 36 NTyl)quinazolin-2-yl)-1H-pyrazole-4- carboxylic acid; 741-(4-(Diethylamino)-6-phenoxyquinazolin- 7.3 NT 812-yl)-1H-pyrazole-4-carboxylic acid; 75 1-(4-(Cyclopropylamino)-6- 6.820 NT phenoxyquinazolin-2-yl)-1H-pyrazole-4- carboxylic acid; 761-(6-Phenoxy-4-((tetrahydro-2H-pyran-4- 6.5 NT 19yl)amino)quinazolin-2-yl)-1H-pyrazole-4- carboxylic acid; 771-(4-(Dimethylamino)-7- 7.4 75 NT phenoxyquinazolin-2-yl)-1H-pyrazole-4-carboxylic acid; 78 1-(7-Phenoxy-4-(pyrrolidin-1- 7.3 38 64yl)quinazolin-2-yl)-1H-pyrazole-4- carboxylic acid; 791-(7-Phenoxy-4-(piperidin-1-yl)quinazolin- 7.0 38 NT2-yl)-1H-pyrazole-4-carboxylic acid; 801-(4-(Dimethylamino)-7-phenylquinazolin- 6.0 NT 7.82-yl)-1H-pyrazole-4-carboxylic acid; 811-(7-Phenyl-4-(pyrrolidin-1-yl)quinazolin- 5.5 NT 102-yl)-1H-pyrazole-4-carboxylic acid; 821-(7-Phenyl-4-(piperidin-1-yl)quinazolin-2- 6.1 NT 4.6yl)-1H-pyrazole-4-carboxylic acid; 831-(4-(Diethylamino)-7-phenoxyquinazolin- 7.7 25 NT2-yl)-1H-pyrazole-4-carboxylic acid; 841-(4-((Cyclohexylmethyl)amino)-7- 6.8 NT 4.6phenoxyquinazolin-2-yl)-1H-pyrazole-4- carboxylic acid; 851-(4-(4-Isopropylpiperidin-1-yl)-7- 6.8 NT 1.7phenoxyquinazolin-2-yl)-1H-pyrazole-4- carboxylic acid; 861-(4-(Cyclopropylamino)-7- 6.3 NT 13phenoxyquinazolin-2-yl)-1H-pyrazole-4- carboxylic acid; 871-(4-(Azepan-1-yl)-7-phenoxyquinazolin- 7.2 NT 202-yl)-1H-pyrazole-4-carboxylic acid; 881-(4-(Diethylamino)-6-(piperidin-1- 7.0 94 122yl)quinazolin-2-yl)-1H-pyrazole-4- carboxylic acid; 891-(4-Morpholino-7-phenoxyquinazolin-2- 6.2 NT 17yl)-1H-pyrazole-4-carboxylic acid; 90 1-(7-Phenoxy-4- 6.3 NT 7.7thiomorpholinoquinazolin-2-yl)-1H- pyrazole-4-carboxylic acid; 911-(4-(4-Fluoropiperidin-1-yl)-7- 6.3 NT 18phenoxyquinazolin-2-yl)-1H-pyrazole-4- carboxylic acid; 921-(4-(Dibutylamino)-7-phenoxyquinazolin- 7.1 NT 4.12-yl)-1H-pyrazole-4-carboxylic acid; 93 1-(4-(Dipropylamino)-7- 7.2 NT43 phenoxyquinazolin-2-yl)-1H-pyrazole-4- carboxylic acid; 941-(4-(Ethyl(methyl)amino)-7- 7.2 NT 83phenoxyquinazolin-2-yl)-1H-pyrazole-4- carboxylic acid; 951-(4-((2-Methoxyethyl)(methyl)amino)-7- 6.8 NT 46phenoxyquinazolin-2-yl)-1H-pyrazole-4- carboxylic acid; 961-(7-Bromo-4-(diethylamino)quinazolin-2- 6.9 NT 72yl)-1H-pyrazole-4-carboxylic acid; 97 1-(4-(Cyclohexylamino)-7- 7.0 NT55 phenoxyquinazolin-2-yl)-1H-pyrazole-4- carboxylic acid; 981-(4-((Cyclopropylmethyl)amino)-7- 6.7 NT 46phenoxyquinazolin-2-yl)-1H-pyrazole-4- carboxylic acid; 991-(4-(tert-Butylamino)-7- 6.3 NT 31phenoxyquinazolin-2-yl)-1H-pyrazole-4- carboxylic acid. 1001-(7-Fluoro-6-(cyclohexyloxy)-4- 6.6 18 NTmorpholinoquinazolin-2-yl)-1H-pyrazole- 4-carboxylic acid. 1011-(7-fluoro-6-(cyclohexyloxy)-4- 7.1 85 NT(dimethylamino)quinazolin-2-yl)-1H- pyrazole-4-carboxylic acid 1021-(7-fluoro-6-(cyclohexyloxy)-4- 7.5 37 NT(pyrrolidin-1-yl)quinazolin-2-yl)-1H- pyrazole-4-carboxylic acid. 1031-(7-fluoro-6-(cyclohexyloxy)-4- 7.3 31 NT(pyrrolidin-1-yl)quinazolin-2-yl)-1H- pyrazole-4-carboxylic acid. 1041-(7-fluoro-6-(cyclohexyloxy)-4- 7.1 49 NT(ethyl(methyl)amino)quinazolin-2-yl)-1H- pyrazole-4-carboxylic acid. 1051-(7-fluoro-6-(cyclohexyloxy)-4-(cyclopropylamino)quinazolin- 7.2 29 NT2-yl)-1H- pyrazole-4-carboxylic acid. 1361-(7-chloro-6-(cyclohexyloxy)-4- 6.7 33 NTmorpholinoquinazolin-2-yl)-1H-pyrazole- 4-carboxylic acid. 1371-(7-chloro-6-(cyclohexyloxy)-4- 7.4 32 NT(dimethylamino)quinazolin-2-yl)-1H- pyrazole-4-carboxylic acid. 1381-(7-chloro-6-(cyclohexyloxy)-4- 7.5 NT NT(diethylamino)quinazolin-2-yl)-1H- pyrazole-4-carboxylic acid. 1391-(7-chloro-6-(cyclohexyloxy)-4-(pyrrolidin- 7.1 NT NT1-yl)quinazolin-2-yl)-1H- pyrazole-4-carboxylic acid 1401-(7-chloro-6-(cyclohexyloxy)-4- 7.2 29 NT(ethyl(methyl)amino)quinazolin-2-yl)-1H- pyrazole-4-carboxylic acid. 1411-(7-chloro-6-(cyclohexyloxy)-4- 7.0 NT NT(cyclopropylamino)quinazolin-2-yl)-1H- pyrazole-4-carboxylic acid. 1601-(7-chloro-6-isopropyl-4- 6.8 28 NTmorpholinoquinazolin-2-yl)-1H-pyrazole- 4-carboxylic acid 1611-(7-chloro-4-(dimethylamino)-6- 7.4 32 NTisopropylquinazolin-2-yl)-1H-pyrazole-4- carboxylic acid. 1621-(7-chloro-4-diethylamino-6- 7.2 40 NTisopropylquinazolin-2-yl)-1H-pyrazole-4- carboxylic acid. 1631-(7-chloro-4-(pyrrolidin-1-yl)-6- 7.3 26 NTisopropylquinazolin-2-yl)-1H-pyrazole-4- carboxylic acid. 1641-(7-chloro-4-(ethyl(methyl)amino)-6- 7.4 57 NTisopropylquinazolin-2-yl)-1H-pyrazole-4- carboxylic acid. 1651-(7-chloro-4-(cyclopropylamino)-6- 7.0 24 NTisopropylquinazolin-2-yl)-1H-pyrazole-4- carboxylic acid 1721-(6-(cyclohexyloxy)-4- 6.4 18 NTmorpholinoquinazolin-2-yl)-1H-pyrazole- 4-carboxylic acid 1731-(6-(cyclohexyloxy)-4- 7.4 62 NT (dimethylamino)quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid. 174 1-(6-(cyclohexyloxy)-4- 7.2 35 NT(diethylamino)quinazolin-2-yl)-1H- pyrazole-4-carboxylic acid. 1751-(6-(cyclohexyloxy)-4-(pyrrolidin-1- 7.2 46 NTyl)quinazolin-2-yl)-1H-pyrazole-4- carboxylic acid 1761-(6-(cyclohexyloxy)-4- 6.8 35 NT (cyclopropylamino)quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid. 177 1-(6-(cyclohexyloxy)-4- 7.3 56 NT(ethyl(methyl)amino)quinazolin-2-yl)-1H- pyrazole-4-carboxylic acid. 1781-(6-benzyl-4-morpholinoquinazolin-2-yl)- 6.5 NT NT1H-pyrazole-4-carboxylic acid 1791-(6-benzyl-4-(dimethylamino)quinazolin- 7.1 NT NT2-yl)-1H-pyrazole-4-carboxylic acid. 1801-(6-benzyl-4-(diethylamino)quinazolin-2- 7.1 NT NTyl)-1H-pyrazole-4-carboxylic acid. 1811-(6-benzyl-4-(pyrrolidin-1-yl)quinazolin- 7.1 NT NT2-yl)-1H-pyrazole-4-carboxylic acid. 182 1-(6-benzyl-4- 7.1 NT NT(cyclopropylamino)quinazolin-2-yl)-1H- pyrazole-4-carboxylic acid. 1831-(6-benzyl-4- 7.2 NT NT (ethyl(methyl)amino)quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid. 184 1-(4-(morpholino)-6-isopropylquinazolin-5.7 24 NT 2-yl)-1H-pyrazole-4-carboxylic acid. 1851-(4-(dimethylamino)-6- 7.0 62 NTisopropylquinazolin-2-yl)-1H-pyrazole-4- carboxylic acid. 1861-(4-(diethylamino)-6-isopropylquinazolin- 7.0 43 NT2-yl)-1H-pyrazole-4-carboxylic acid 187 1-(6-isopropyl-4-(pyrrolidin-1-6.8 28 NT yl)quinazolin-2-yl)-1H-pyrazole-4- carboxylic acid. 1881-(4-(cyclopropylamino)-6- 6.0 35 NTisopropylquinazolin-2-yl)-1H-pyrazole-4- carboxylic acid 1891-(6-isopropyl-4- 6.8 36 NT (ethyl(methyl)amino)quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid.

What is claimed is:
 1. A compound of the formula (I):

wherein: n is 0-3 R¹ is a member independently selected from the groupconsisting of halo, —O—R^(c), —C₁₋₄alkyl, cyclohexyl, phenyl optionallysubstituted with —C₁₋₄alkyl, benzyl optionally substituted with—C₁₋₄alkyl, and —NR^(a)R^(b); R^(a) is H and R^(b) is benzyl optionallysubstituted with —C₁₋₄alkyl, or R^(a) and R^(b) are taken together withthe nitrogen to which they are attached to form a piperidine ring; R^(c)is cyclohexyl, phenyl optionally substituted with one or more R^(d)members; R^(d) is a member independently selected from the groupconsisting of —H, halo, and —C₁₋₄alkyl; R² is a member independentlyselected from the group consisting of —H, and —C₁₋₄alkyl, R³ is a memberindependently selected from the group consisting of —H, —C₁₋₄alkyloptionally substituted with —OCH₃ or —N(C₁₋₄alkyl)₂, cyano, —SO₂CH₃,tetrahydropyran, —(CH₂)_(m)C₃₋₈cycloalkyl, —(CH₂)_(m)phenyl optionallysubstituted with one or more halo, or —C₁₋₄alkyl; m is 0-1; R² and R³can be taken together with the nitrogen to which they are attached toform a 4 to 7 membered heterocycloalkyl ring optionally containing O, N,S optionally substituted with —OH, cyano, halo, —N—C(O)C₁₋₄alkyl, and—C₁₋₄alkyl; and enantiomers, diastereomers, racemates, andpharmaceutically acceptable salts thereof.
 2. A compound as defined inclaim 1, where R¹ is a member independently selected from the groupconsisting of bromo, chloro, fluoro, methyl, isopropyl, cyclohexyl,cyclohexyloxy, phenyl, 2-methylphenyl, benzyl, phenoxy, 4-chlorophenoxy,2,6-dimethyl-phenoxy, piperidinyl, and (2,6-dimethylbenzyl)amino.
 3. Acompound of claim 1 where n is
 1. 4. A compound of claim 1 where n is 2.5. A compound of claim 1 where n is
 3. 6. A compound as defined in claim1, where R^(a) is H and R^(b) is 2,6-dimethylbenzyl.
 7. A compound asdefined in claim 1, where R^(c) is a member selected from the groupconsisting of phenyl, cyclohexyl, 4-chlorophenyl, and2,6-dimethyl-phenyl.
 8. A compound as defined in claim 1, where R^(d) isa member selected from the group consisting of —H, chloro, and —CH₃. 9.A compound as defined in claim 1, where R² is —H and R³ is a memberselected from the group consisting of H, cyano, methyl, ethyl, propyl,tertbutyl, cyclopropyl, cyclopropylmethyl, tetrahydropyranyl,cyclohexylmethyl, phenyl, 2-chlorophenyl, 2,6-dimethylbenzyl, and—SO₂CH₃.
 10. A compound as defined in claim 1, where R² is selected fromthe group consisting of methyl, ethyl, propyl, and butyl.
 11. A compoundas defined in claim 1, where R³ is selected from the group consisting ofmethyl, ethyl, propyl, butyl, tertbutyl, 2-methoxyethyl,2-methoxy-1-methyl-ethyl and diethylamino-ethyl.
 12. A compound asdefined in claim 1, where R² and R³ are taken together with the nitrogento which they are attached to form pyrrolidine, piperidine,4-methyl-1,4-diazepane, thiomorpholine, 4-hydroxypiperidine, morpholine,4-acetamidopiperidine, 4-cyanopiperidine, 4-fluoropiperidine, azepane,or 4-isopropylpiperidine.
 13. A compound as defined in claim 1, where nis 2, R¹ is a member independently selected from the group consisting ofhalo, cyclohexyl, and 2,6-dimethyl-phenoxy, and R² and R³ are C₁₋₄alkyl,or R² and R³ are taken together with the nitrogen to which they areattached to form morpholine.
 14. A pharmaceutical composition comprisinga pharmaceutically acceptable excipient and an effective amount ofcompound having PHD inhibitor activity of formula (I):

wherein: n is 0-3 R¹ is a member independently selected from the groupconsisting of halo, —O—R^(c), —C₁₋₄alkyl, cyclohexyl, phenyl optionallysubstituted with —C₁₋₄alkyl, benzyl optionally substituted with—C₁₋₄alkyl, and —NR^(a)R^(b); R^(a) is H and R^(b) is benzyl optionallysubstituted with —C₁₋₄alkyl, or R^(a) and R^(b) are taken together withthe nitrogen to which they are attached to form a piperidine ring; R^(c)is cyclohexyl, phenyl optionally substituted with one or more R^(d)members; R^(d) is a member independently selected from the groupconsisting of —H, halo, and —C₁₋₄alkyl; R² is a member independentlyselected from the group consisting of —H, and —C₁₋₄alkyl, R³ is a memberindependently selected from the group consisting of —H, —C₁₋₄alkyloptionally substituted with —OCH₃ or —N(C₁₋₄alkyl)₂, cyano, —SO₂CH₃,tetrahydropyran, —(CH₂)_(m)C₃₋₈cycloalkyl, —(CH₂)_(m)phenyl optionallysubstituted with one or more halo, or —C₁₋₄alkyl; m is 0-1; R² and R³can be taken together with the nitrogen to which they are attached toform a 4 to 7 membered heterocycloalkyl ring optionally containing O, N,S optionally substituted with —OH, cyano, halo, —N—C(O)C₁₋₄alkyl, and—C₁₋₄alkyl; and enantiomers, diastereomers, racemates, andpharmaceutically acceptable salts thereof.
 15. A pharmaceuticalcomposition comprising an effective amount of at least on chemicalentity of claim
 1. 16. A method for the treatment of anemia, hypoxia,ischemia, peripheral vascular disease, myocardial infarction, stroke,diabetes, obesity, inflammatory bowel disease, ulcerative colitis,Crohn's disease, wounds, infection, burns and bone fracture comprisingthe step of administering to a patient in need thereof a therapeuticallyeffective amount of compound having PHD inhibitor activity of formula(I):

wherein: n is 0-3 R¹ is a member independently selected from the groupconsisting of halo, —O—R^(c), —C₁₋₄alkyl, cyclohexyl, phenyl optionallysubstituted with —C₁₋₄alkyl, benzyl optionally substituted with—C₁₋₄alkyl, and —NR^(a)R^(b); R^(a) is H and R^(b) is benzyl optionallysubstituted with —C₁₋₄alkyl, or R^(a) and R^(b) are taken together withthe nitrogen to which they are attached to form a piperidine ring; R^(c)is cyclohexyl, phenyl optionally substituted with one or more R^(d)members; R^(d) is a member independently selected from the groupconsisting of —H, halo, and —C₁₋₄alkyl; R² is a member independentlyselected from the group consisting of —H, and —C₁₋₄alkyl, R³ is a memberindependently selected from the group consisting of —H, —C₁₋₄alkyloptionally substituted with —OCH₃ or —N(C₁₋₄alkyl)₂, cyano, —SO₂CH₃,tetrahydropyran, —(CH₂)_(m)C₃₋₈cycloalkyl, —(CH₂)_(m)phenyl optionallysubstituted with one or more halo, or —C₁₋₄alkyl; m is 0-1; R² and R³can be taken together with the nitrogen to which they are attached toform a 4 to 7 membered heterocycloalkyl ring optionally containing O, N,S optionally substituted with —OH, cyano, halo, —N—C(O)C₁₋₄alkyl, and—C₁₋₄alkyl; and enantiomers, diastereomers, racemates, andpharmaceutically acceptable salts thereof.
 17. A method for treating ahypoxic disorder comprising the step of administering to a patient inneed thereof a therapeutically effective amount of compound having PHDinhibitor activity of formula (I):

wherein: n is 0-3 R¹ is a member independently selected from the groupconsisting of halo, —O—R^(c), —C₁₋₄alkyl, cyclohexyl, phenyl optionallysubstituted with —C₁₋₄alkyl, benzyl optionally substituted with—C₁₋₄alkyl, and —NR^(a)R^(b); R^(a) is H and R^(b) is benzyl optionallysubstituted with —C₁₋₄alkyl, or R^(a) and R^(b) are taken together withthe nitrogen to which they are attached to form a piperidine ring; R^(c)is cyclohexyl, phenyl optionally substituted with one or more R^(d)members; R^(d) is a member independently selected from the groupconsisting of —H, halo, and —C₁₋₄alkyl; R² is a member independentlyselected from the group consisting of —H, and —C₁₋₄alkyl, R³ is a memberindependently selected from the group consisting of —H, —C₁₋₄alkyloptionally substituted with —OCH₃ or —N(C₁₋₄alkyl)₂, cyano, —SO₂CH₃,tetrahydropyran, —(CH₂)_(m)C₃₋₈cycloalkyl, —(CH₂)_(m)phenyl optionallysubstituted with one or more halo, or —C₁₋₄alkyl; m is 0-1; R² and R³can be taken together with the nitrogen to which they are attached toform a 4 to 7 membered heterocycloalkyl ring optionally containing O, N,S optionally substituted with —OH, cyano, halo, —N—C(O)C₁₋₄alkyl, and—C₁₋₄alkyl; and enantiomers, diastereomers, racemates, andpharmaceutically acceptable salts thereof.
 18. The method of claim 17,wherein said hypoxic disorder is selected from the group consisting ofanemia, ischemia, stroke, myocardial infarction, and coronary arterydisease.
 19. A method for treating diabetes comprising administering atherapeutically effective amount of a compound of claim 1 to a patientin need thereof.
 20. A method for wound treatment comprisingadministering a therapeutically effective amount of a compound of claim1 to a patient in need thereof.
 21. A method for treating a metabolicdisorder comprising administering a therapeutically effective amount ofa compound of claim 1 to a patient in need thereof.
 22. The method ofclaim 21 wherein said metabolic disorder is obesity or diabetes.